Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof

ABSTRACT

Novel aryl, heteroaryl, and non-aromatic heterocyle substituted tetrahydroisoquinolines are described in the present invention. These compounds are used in the treatment of various neurological and physiological disorders. Methods of making these compounds are also described in the present invention.

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/177,464, filed May 12, 2009, which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, methods forthe treatment of various neurological and psychological disorders, andthe use of the compounds in combination therapy. In particular, thepresent invention relates to such compounds, compositions, and methods,where the compounds are novel aryl, heteroaryl, and heterocyclesubstituted tetrahydroisoquinoline derivatives. Methods of making thesecompounds are also described in the present invention.

BACKGROUND OF THE INVENTION

Monoamine reuptake inhibitors elevate extracellular levels of serotonin(5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by bindingto one or more of the transporters responsible for reuptake, namely theserotonin transporter (SERT), the norepinephrine transporter (NET) andthe dopamine transporter (DAT), thereby blocking reuptake of theneurotransmitter(s) from the synaptic cleft. Monoamine reuptakeinhibitors are an established drug class that has proven utility for thetreatment of a number of CNS disorders especially major depressivedisorder (MDD).

Since the introduction of tricyclic antidepressants (TCAs) almost 50years ago, monoamine reuptake inhibitors with greatly improved safetyprofiles have significantly enhanced the treatment of depression.Although TCAs are very effective antidepressants, cardiovascular,anticholinergic and sedative side effects are common due to theinteraction of TCAs with muscarinic, histaminic and adrenergicreceptors. The revolutionary introduction of selective serotoninreuptake inhibitors (SSRIs) in the 1980s allowed a much larger patientpopulation to be treated because of the highly improved safety profile.Over the past decades, inhibitors that selectively block the reuptake ofNE or DA, or two of the three neurotransmitters simultaneously, havebecome available for the treatment of CNS disorders includingdepression, anxiety, obsessive compulsive disorder (OCD), attentiondeficit hyperactivity disorder (ADHD), pain and urinary incontinence.Two representative recent reviews (Liu and Molino, Annual Reports inMedicinal Chemistry, 42:13 (2007); Walter, Drug Dev. Res., 65:97 (2005))on monoamine reuptake inhibitors summarized the history and recentdevelopment in the monoamine reuptake inhibitor area.

Currently, the major effort in the field of monoamine reuptakeinhibitors is focused on improving antidepressant efficacy since 30-40%of patients do not respond to treatment with currently availableantidepressants. An additional major objective is to enhance the onsetof action. Current antidepressants typically require 2-6 weeks oftreatment before clinical efficacy is seen. Clinical trials exploringaugmentation strategies, in which a DA reuptake inhibitor or a dualNE/DA reuptake inhibitor is combined with an SSRI, have resulted inimproved efficacy in depressed patients refractory to SSRI treatmentalone (Patkar et. al, J. Clin. Psychopharmacol., 26:653 (2006); Zisooket al, Biol. Psychiat., 59:203 (2006)). The improved results fromclinical trials such as these serve to justify the considerable focus onthe development of inhibitors that simultaneously block the reuptake of5-HT, NE and DA. Because of the continued need for better drugs to treatdepression and the opportunities for new clinical indications, effortsto discover novel monoamine reuptake inhibitors continue unabated.

Methylphenidate, currently used for the treatment of attentiondeficit-hyperactivity disorder, is known to be selective for inhibitionof the DAT. Also, U.S. Pat. No. 5,444,070 discloses selective inhibitorsof dopamine reuptake as treatments for Parkinson's disease, drugaddiction or abuse including cocaine and amphetamines.

Selective norepinephrine reuptake inhibitors (NARI) have also beendisclosed. U.S. Pat. No. 6,352,986 describes methods of treatingattention deficit-hyperactivity disorder (ADHD), addictive disorders,and psychoactive substance use disorders with Reboxetine. Also,Atomoxetine (STRATTERA®) is currently marketed as a selective NETreuptake inhibitor for ADHD.

The use of selective serotonin reuptake inhibitors (SSRI) has been shownto be effective in treating depressive disorders. Sertraline,citalopram, escitalopram, paroxetine, fluoxetine and fluvoxamine arewell known examples of SSRIs used to treat disorders such as depression,obsessive compulsive disorder, and panic attacks. There are severalknown difficulties with the SSRI class of therapeutics, including theslow onset of action, unwanted side effects, and the existence of asignificant subset of the population that is not responsive to SSRItherapy. Recent effort in the clinical development of new SSRIs hasfocused on the treatment of premature ejaculation (PE) by takingadvantage of the ejaculation-delaying side effects of SSRIs. AlthoughSSRIs have been prescribed off-label to treat this condition, an SSRIwith rapid onset of action and rapid clearance could be preferred foron-demand treatment of PE. Dapoxetine (LY210448, 6), an SSRIstructurally related to fluoxetine with a shorter half-life, wasreported to be an effective and generally well tolerated treatment formen with moderate-to-severe PE in clinical trials (Feret, Formulary,40:227 (2005); Pryor et al, Lancet, 368:929 (2006)).

Selective inhibitors of DAT, NET, and SERT reuptake may also beco-administered with each other or with other drugs. U.S. Pat. No.5,532,244 discloses the use of serotonin reuptake inhibitors incombination with a serotonin 1A antagonist for the treatment ofobsessive-compulsive disorder, depression, and obesity. The use of aserotonin or norepinephrine reuptake inhibitor in combination with aneurokinin-1 receptor antagonist has been disclosed in U.S. Pat. No.6,121,261 for the treatment of ADHD. U.S. Pat. No. 4,843,071 disclosesthe use of a norepinephrine reuptake inhibitor in combination with anorepinephrine precursor in the treatment of obesity, drug abuse, ornarcolepsy. U.S. Pat. No. 6,596,741 discloses the use of a NE, DA, or5-HT inhibitor with either a neurokinin-1 receptor antagonist or aserotonin-1A antagonist for the treatment of a wide variety ofconditions.

Also advantageous is the use of compounds that inhibit one or more ofthe neurotransmitters at the same time. The antidepressant qualities ofthe dual NET and SERT reuptake inhibitor duloxetine is disclosed inEuropean Patent No. EP 273658. Venlafaxine is disclosed in U.S. Pat. No.4,535,186 as a reuptake inhibitor of both NE and 5-HT for the treatmentof depressive disorders. U.S. Pat. No. 6,635,675 discloses the use ofthe dual NE and 5-HT reuptake inhibitor milnacipran for the treatment ofchronic fatigue syndrome and fibromyalgia syndrome. In addition, dual NEand 5-HT reuptake inhibitors are also disclosed in U.S. Pat. No.6,136,083 for the treatment of depression. It is also recognized thatcompounds which inhibit the reuptake of NE, DA, and 5-HT in varyingratios not specifically mentioned here would also be advantageous.

As the first SNRI drug approved, venlafaxine has become one of thefirst-line choices for depression and anxiety disorder. An activemetabolite, desvenlafaxine, is also under clinical development for thetreatment of major depressive disorders. Preclinical studies alsoindicate that desvenlafaxine may be effective in relieving vasomotorsymptoms associated with menopause (e.g., hot flashes and night sweats)(Sorbera, et al, Drugs of Future., 31:304 (2006); Albertazzi, J. Br.Menopause Soc., 12:7 (2006)). Desvenlafaxine is reported to be inclinical development for the treatment of fibromyalgia and neuropathicpain, as well as vasomotor symptoms associated with menopause.

In addition to treating major depressive disorder, duloxetine wasapproved as the first agent for the treatment of painful diabeticneuropathy in the U.S. It also has been used for stress urinaryincontinence in women in Europe. In 2007, duloxetine was approved forthe treatment of generalized anxiety disorder in the U.S. Most recently,it was approved by the FDA for the management of fibromyalgia.

Milnacipran is currently available for use as an antidepressant inseveral countries outside the U.S. It is also under clinical developmentto assess its potential role in the treatment of fibromyalgia syndrome.

After more than a decade of use, bupropion, is considered a safe andeffective antidepressant, suitable for use as first-line treatment. Inaddition, it is approved for smoking cessation and seasonal affectivedisorder. It is also prescribed off-label to treat the sexualdysfunction induced by SSRIs. Bupropion is often referred to as anatypical antidepressant. It has much lower affinity for the monoaminetransporters compared with other monoamine reuptake inhibitors. Themechanism of action of bupropion is still uncertain but may be relatedto inhibition of dopamine and norepinephrine reuptake transporters as aresult of active metabolites. In a recently reported clinical trial,bupropion extended release (XL) had a sexual tolerability profilesignificantly better than that of escitalopram with similar remissionrates and Hospital Anxiety and Depression (HAD) total scores in patientswith major despressive disorder (Clayton et al. J. Clin. Psychiatry,67:736 (2006)).

Treating illnesses by inhibiting the reuptake of all three of themonoamines either through combination therapy or “triple inhibitors” mayhave clinical benefit as well. Triple inhibitors are considered to bethe next generation antidepressant (Liang and Richelson, PrimaryPsychiatry, 15(4):50 (2008)). Rationale for inclusion of a dopamineenhancing component in anti-depressant therapy includes observeddeficits in dopaminergic function, the success of combination therapywith dopamine agonists and traditional anti-depressants, and anincreased sensitivity in dopamine receptors due to chronicanti-depressant administration (Skolnick et al., Life Sciences,73:3175-3179 (2003)). Combination therapy with an SSRI and anoradrenaline and dopamine reuptake inhibitor was shown to be moreefficacious in patients with treatment-resistant depression (Lam et al,J. Clin. Psychiatry, 65(3):337-340 (2004)). Clinical studies using thecombination of bupropion and an SSRI or SNRI have showed improvedefficacy for the treatment of MDD in patients refractory to thetreatment with SSRIs, SNRIs, or bupropion alone (Zisook et al, Biol.Psychiat., 59:203 (2006); Papkostas, Depression and Anxiety, 23:178-181(2006); Trivedi et al, New Engl. J. Med., 354:1243 (2006)). Otherstudies using methylphenidate, both immediate release and extendedrelease formula, have shown it to be effective as an augmenting agent intreatment-resistant depression (Patkar et al, J. Clin. Psychopharmacol.,26:653 (2006); Masand et al, Depression and Anxiety, 7:89 (1998)). Inaddition, the combination of bupropion-SR with either SSRIs ornorepinephrine and dopamine reuptake inhibitors was found to induce lesssexual dysfunction than monotherapy (Kennedy et al, J. Clin. Psychiatry,63(3):181-186 (2002)). As such, inhibitory activity against DA reuptake,in addition to NE and 5-HT reuptake, is expected to provide a more rapidonset of anti-depressant effect than other mixed inhibitors which areselective for NET and SERT over DAT. PCT International Publication Nos.WO 03/101453 and WO 97/30997 disclose a class of compounds which areactive against all three monoamine transporters. Also, PCT InternationalPatent Publication No. WO 03/049736 discloses a series of 4-substitutedpiperidines, each of which displays similar activity against DA, NE, and5-HT transporters. Bicyclo[2.2.1]heptanes (Axford et al., Bioorg. Med.Chem. Lett., 13:3277-3280 (2003)) and azabicyclo[3.1.0]hexanes (Skolnicket al., Eur. J. Pharm., 461:99-104 (2003)) are also described as tripleinhibitors of the three monoamine transporters.1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane has been shown to beefficacious in treating depression in clinical trials (Beer et al, J.Clin. Pharmacol., 44:1360-1367 (2004)). Current widely used anti-obesitydrug sibutramine is believed to work through the inhibition of all threetransporters DAT, SERT, and NET (Ryan, Pharmacotherapy of Obesity,245-266 (2004)).

Recent drug approvals with SNRIs for treatment of fibromyalgia anddiabetic neuropathy reinforce the utility of this drug class in thetreatment of neuropathic pain. Other largely untapped areas which remainto be exploited with this drug class include sexual dysfunction, such aspremature ejaculation, irritable bowel syndrome, obesity,neurodegenerative diseases such as Parkinson's disease, restless legsyndrome, and substance abuse and addiction.

There is still a large need for compounds that block the reuptake ofnorepinephine, dopamine, and serotonin and treat various neurologicaland psychological disorders.

The present invention is directed achieving this objective.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I):

wherein:the carbon atom designated * is in the R or S configuration;R¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, C₁-C₆haloalkyl, or gem-dialkyl of which eachalkyl is C₁-C₄;R² is H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹²,C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, andphenyl which is optionally substituted 1-3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰;R³ is an aryl selected from the group consisting of phenyl, naphthyl,indanyl, and indenyl, or a heteroaryl selected from the group consistingof pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, furo[2,3-b]pyrazinyl,imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-a][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl, and3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or a non-aromatic heterocycleselected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl,piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl,2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino,1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl;wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionallysubstituted from 1 to 4 times with substituents as defined below in R¹⁴;R⁴, R⁵ and R⁶ and R⁷ are each independently H or are selected from thegroup consisting of halogen, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN, —C(O)R¹²,—C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, and wherein each of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from C₁-C₃ alkyl,halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted1-3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰;R⁸ is H, C₁-C₆ alkyl, halogen or OR¹¹;R⁹ and R¹⁰ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl,or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to3 times with a substituent selected independently at each occurrencethereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy;or R⁹ and R¹⁰ are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring;R¹¹ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl, or benzyl, whereinphenyl or benzyl is optionally substituted 1 to 3 times with halogen,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R¹² is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;or R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring, with the provisothat only one of R⁹ and R¹⁰ or R¹¹ and R¹² are taken together with thenitrogen to which they are attached to form a piperidine, pyrrolidine,piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;R¹³ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;n is 0, 1, or 2; and,R¹⁴ is independently selected at each occurrence from a substituentselected from the group consisting of halogen, —NO₂, —OR¹¹, —NR¹¹R¹²,—NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl where C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from the group consisting of C₁-C₃ alkyl, halogen,Ar, —CN, —OR⁹, and —NR⁹R¹⁰;or an oxide thereof, a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates experimental and simulated powder X-Ray diffraction(PXRD) patterns (CuKα λ=1.54178 Å at T=room temperature) of crystallineForm SA-1.

FIG. 2 illustrates the differential scanning calorimetry (DSC) patternof Form SA-1.

FIG. 3 illustrates thermogravimetric analysis (TGA) of Form SA-1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I):

wherein:the carbon atom designated * is in the R or S configuration;R¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, C₁-C₆haloalkyl, or gem-dialkyl of which eachalkyl is C₁-C₄;R² is H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹²,C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇cycloalkylalkyl and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹R¹⁰;R³ is an aryl selected from the group consisting of phenyl, naphthyl,indanyl, and indenyl, or a heteroaryl selected from the group consistingof pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, furo[2,3-b]pyrazinyl,imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-a][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl, and3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or a non-aromatic heterocycleselected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl,piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl,2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino,1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl;wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionallysubstituted from 1 to 4 times with substituents as defined below in R¹⁴;R⁴, R⁵ and R⁶ and R⁷ are each independently H or are selected from thegroup consisting of halogen, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN, —C(O)R¹²,—C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, and wherein each of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from the groupconsisting of C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenyl whichis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰;R⁸ is H, C₁-C₆ alkyl, halogen or OR¹¹;R⁹ and R¹⁰ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl,or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3times with a substituent selected independently at each occurrencethereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy;or R⁹ and R¹⁰ are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring;R¹¹ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl, or benzyl, wherephenyl or benzyl is optionally substituted 1 to 3 times with halogen,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R¹² is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, where phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;or R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring, with the provisothat only one of R⁹ and R¹⁰ or R¹¹ and R¹² are taken together with thenitrogen to which they are attached to form a piperidine, pyrrolidine,piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;R¹³ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;n is 0, 1, or 2; andR¹⁴ is independently selected at each occurrence from a substituentselected from the group consisting of halogen, —NO₂, —OR¹¹, —NR¹¹R¹²,—NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, where C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from the group consisting of C₁-C₃ alkyl, halogen,Ar, —CN, —OR⁹, and —NR⁹R¹⁰;or an oxide thereof, a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

The term “alkyl” means an aliphatic hydrocarbon group which may bestraight or branched having about 1 to about 6 carbon atoms in thechain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl are attached to a linear alkyl chain. Exemplaryalkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, n-pentyl, and 3-pentyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl.

The term “aryl” means an aromatic monocyclic or multicyclic ring systemof 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms.Representative aryl groups include phenyl and naphthyl.

The term “heteroaryl” means an aromatic monocyclic or multicyclic ringsystem of about 5 to about 14 ring atoms, preferably about 5 to about 10ring atoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example, nitrogen, oxygen, or sulfur.In the case of multicyclic ring system, only one of the rings needs tobe aromatic for the ring system to be defined as “Heteroaryl”. Preferredheteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia,or thio before heteroaryl means that at least a nitrogen, oxygen, orsulfur atom, respectively, is present as a ring atom. A nitrogen atom ofa heteroaryl is optionally oxidized to the corresponding N-oxide.Representative heteroaryls include pyridyl, 2-oxo-pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-a][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl,3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like.

The term “non-aromatic heterocycle” means a non-aromatic monocyclicsystem containing 3 to 10 atoms, preferably 4 to about 7 carbon atoms,in which one or more of the atoms in the ring system is/are element(s)other than carbon, for example, nitrogen, oxygen, or sulfur.Representative non-aromatic heterocycle groups include pyrrolidinyl,2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl,2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino,thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl,tetrohydro-2H-oxazinyl, and the like.

The term “alkoxy” means an alkyl-O— group wherein the alkyl group is asherein described. Exemplary alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy and heptoxy.

A compound with a hydroxy group drawn next to a nitrogen on aheterocycle can exist as the “keto” form. For example,3-(2-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)propanoic acid can existas 3-(2-oxo-2,3-dihydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)propanoicacid.

The term “compounds of the invention”, and equivalent expressions, aremeant to embrace compounds of general formula (I) as hereinbeforedescribed, which expression includes the prodrugs, the pharmaceuticallyacceptable salts, and the solvates, e.g. hydrates, where the context sopermits. Similarly, reference to intermediates, whether or not theythemselves are claimed, is meant to embrace their salts, and solvates,where the context so permits. For the sake of clarity, particularinstances when the context so permits are sometimes indicated in thetext, but these instances are purely illustrative and it is not intendedto exclude other instances when the context so permits.

The term “cycloalkyl” means a non-aromatic mono- or multicyclic ringsystem of about 3 to about 7 carbon atoms, preferably of about 5 toabout 7 carbon atoms.

Exemplary monocyclic cycloalkyls include cyclopentyl, cyclohexyl,cycloheptyl, and the like.

The term “cycloalkylalkyl” means an cycloalkyl-alkyl-group in which thecycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkylgroups include cyclopropylmethyl and cyclopentylmethyl.

The term “gem-dialkyl” means two alkyl groups that substitute the twohydrogen atoms of a methylene group

The term “gem-dimethyl” means two methyl groups that substitute the twohydrogen atoms of a methylene group.

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.

The term “haloalkyl” means both branched and straight-chain alkylsubstituted with one or more halogen, wherein the alkyl group is asherein described.

The term “haloalkoxy” means a C₁₋₄ alkoxy group substituted by at leastone halogen atom, wherein the alkoxy group is as herein described.

The term “substituted” or “substitution” of an atom means that one ormore hydrogen on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded.

“Unsubstituted” atoms bear all of the hydrogen atoms dictated by theirvalency. When a substituent is keto (i.e., =0), then two hydrogens onthe atom are replaced. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds; by“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “pharmaceutically acceptable salts” means the relativelynon-toxic, inorganic, and organic acid addition salts, and base additionsalts, of compounds of the present invention. These salts can beprepared in situ during the final isolation and purification of thecompounds. In particular, acid addition salts can be prepared byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Exemplary acid addition salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactiobionate, sulphamates,malonates, salicylates, propionates, methylene-bis-b-hydroxynaphthoates,gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates,ethanesulphonates, benzenesulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like(see, for example, Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci.,66:1-9 (1977) and Remington's Pharmaceutical Sciences, 17th ed., MackPublishing Company, Easton, Pa., 1985, p. 1418, which are herebyincorporated by reference in their entirety). Base addition salts canalso be prepared by separately reacting the purified compound in itsacid form with a suitable organic or inorganic base and isolating thesalt thus formed. Base addition salts include pharmaceuticallyacceptable metal and amine salts. Suitable metal salts include thesodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts.The sodium and potassium salts are preferred. Suitable inorganic baseaddition salts are prepared from metal bases which include, for example,sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide,and zinc hydroxide. Suitable amine base addition salts are prepared fromamines which have sufficient basicity to form a stable salt, andpreferably include those amines which are frequently used in medicinalchemistry because of their low toxicity and acceptability for medicaluse, such as ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, e.g., lysine andarginine, dicyclohexylamine, and the like.

The term “pharmaceutically acceptable prodrugs” as used herein meansthose prodrugs of the compounds useful according to the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” means compoundsthat are rapidly transformed in vivo to yield the parent compound of theabove formula, for example by hydrolysis in blood. Functional groupswhich may be rapidly transformed, by metabolic cleavage, in vivo form aclass of groups reactive with the carboxyl group of the compounds ofthis invention. They include, but are not limited to, such groups asalkanoyl (such as acetyl, propionyl, butyryl, and the like),unsubstituted and substituted aroyl (such as benzoyl and substitutedbenzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (suchas trimethyl- and triethysilyl), monoesters formed with dicarboxylicacids (such as succinyl), and the like. Because of the ease with whichthe metabolically cleavable groups of the compounds useful according tothis invention are cleaved in vivo, the compounds bearing such groupsact as pro-drugs. The compounds bearing the metabolically cleavablegroups have the advantage that they may exhibit improved bioavailabilityas a result of enhanced solubility and/or rate of absorption conferredupon the parent compound by virtue of the presence of the metabolicallycleavable group. A thorough discussion of prodrugs is provided in thefollowing: Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985);Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396 (1985); A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design andApplications of Prodrugs” p. 113-191 (1991); Advanced Drug DeliveryReviews, H. Bundgard, 8, p. 1-38 (1992); Journal of PharmaceuticalSciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692(1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and Bioreversible Carriers in DrugDesign, Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press (1987), which are incorporated herein by reference intheir entirety. Examples of prodrugs include, but are not limited to,acetate, formate, and benzoate derivatives of alcohol and aminefunctional groups in the compounds of the invention.

The term “therapeutically effective amounts” is meant to describe anamount of compound of the present invention effective in increasing thelevels of serotonin, norepinephrine, or dopamine at the synapse and thusproducing the desired therapeutic effect. Such amounts generally varyaccording to a number of factors well within the purview of ordinarilyskilled artisans given the description provided herein to determine andaccount for. These include, without limitation: the particular subject,as well as its age, weight, height, general physical condition, andmedical history, the particular compound used, as well as the carrier inwhich it is formulated and the route of administration selected for it;and, the nature and severity of the condition being treated.

The term “pharmaceutical composition” means a composition comprising acompound of formula (I) and at least one component comprisingpharmaceutically acceptable carriers, diluents, adjuvants, excipients,or vehicles, such as preserving agents, fillers, disintegrating agents,wetting agents, emulsifying agents, suspending agents, sweeteningagents, flavoring agents, perfuming agents, antibacterial agents,antifungal agents, lubricating agents and dispensing agents, dependingon the nature of the mode of administration and dosage forms. Examplesof suspending agents include ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monosterate andgelatin. Examples of suitable carriers, diluents, solvents, or vehiclesinclude water, ethanol, polyols, suitable mixtures thereof, vegetableoils (such as olive oil), and injectable organic esters such as ethyloleate. Examples of excipients include lactose, milk sugar, sodiumcitrate, calcium carbonate, and dicalcium phosphate. Examples ofdisintegrating agents include starch, alginic acids, and certain complexsilicates. Examples of lubricants include magnesium stearate, sodiumlauryl sulphate, talc, as well as high molecular weight polyethyleneglycols.

The term “pharmaceutically acceptable” means it is, within the scope ofsound medical judgement, suitable for use in contact with the cells ofhumans and lower animals without undue toxicity, irritation, allergicresponse and the like, and are commensurate with a reasonablebenefit/risk ratio.

The term “pharmaceutically acceptable dosage forms” means dosage formsof the compound of the invention, and includes, for example, tablets,dragees, powders, elixirs, syrups, liquid preparations, includingsuspensions, sprays, inhalants tablets, lozenges, emulsions, solutions,granules, capsules, and suppositories, as well as liquid preparationsfor injections, including liposome preparations. Techniques andformulations generally may be found in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., latest edition.

One preferred embodiment of the present invention is the compound offormula (I), wherein R¹ is H, C₁-C₆ alkyl, or gem-dialkyl, preferablywherein R¹ is H or gem-dimethyl.

Another preferred embodiment of the invention is the compound of formula(I), wherein R² is H, halogen, —OR¹¹, —S(O)₂R¹², —CN, —C(O)R¹²,—C(O)NR¹¹R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl, more preferably Hor halogen.

Another preferred embodiment of the present invention is the compound offormula (I), wherein R³ is optionally substituted aryl, heteroaryl, ornon-aromatic heterocycle group.

Another more preferred embodiment of the present invention is thecompound of formula (I), wherein R³ is phenyl, or heteroaryl selectedfrom the group consisting of pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl,pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl,pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl,benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl,benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl,pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl,benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl,quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, furo[2,3-b]pyrazinyl,imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-a][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl, and3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or non-aromatic heterocycleselected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl,piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl,2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino,1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl;wherein the phenyl, heteroaryl or non-aromatic heterocycle is optionallysubstituted from 1 to 4 times with substituents as defined in R¹⁴;

A further more preferred embodiment of the present invention is thecompound of formula (I), wherein R³ is 1,2,4-oxadiazol-3-yl,3,5-dimethylisoxazol-4-yl, 1H-pyrazol-3-yl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl,4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl,pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3-yl,6-methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl,6-(difluoromethyl)pyridazin-3-yl,6-(difluoromethoxy)methyl)pyridazin-3-yl, 6-aminopyridazin-3-yl,(6-(hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-3-yl,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl,3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl, 6-aminopyrazin-2-yl,2-oxopyridin-1(2H)-yl, 6-oxo-1,6-dihydropyridazin-3-yl,6-oxopyridazin-1(6H)-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl,[1,2,4]triazolo[1,5-a]pyridin-6-yl,3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl,3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,[1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl,3,3-dimethyl-2-oxoindolin-5-yl, 3,3-dimethyl-2-oxoindolin-6-yl,3-methyl-[1,2,4]-triazolo[4,3-b]-pyridazinyl, or[1,2,4]triazolo[4,3-b]-pyridazinyl, each of which is optionallysubstituted from 1 to 4 times with substituents as defined in R¹⁴.

Another more preferred embodiment of the present invention is thecompound of formula (I), wherein R⁴, R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of H, halogen, —OR¹¹,—NR¹¹R¹², —NR¹¹C(O)R¹², S(O)₂R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹², andoptionally substituted C₁-C₆ alkyl.

Another more preferred embodiment of the present invention is thecompound of formula (I), wherein R⁴ is H, C₁-C₆ alkyl, OH, F, Cl, OH, orOCH₃, more particularly H or F.

Another more preferred embodiment of the present invention is thecompound of formula (I), wherein R⁷ is H.

Another more preferred embodiment of the present invention is thecompound of formula (I), wherein R⁵ and R⁶ are each independentlyselected from the group consisting of H, F, Cl, OH, OCH₃, and CH₃, moreparticularly, Cl.

Another more preferred embodiment of the present invention is thecompound of formula (I), wherein R⁸ is H, OH, CH₃, or F.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein:

R¹ is H, C₁-C₆ alkyl, or gem-dialkyl;

R² is H, halogen, —OR¹¹, —S(O)₂R¹², C₁-C₆ alkyl, or substituted C₁-C₆alkyl;

R³ is aryl, heteroaryl, or non-aromatic heterocycle;

R⁴ is H, F, or Cl; and

R⁵, R⁶ and R⁷ are each independently H, halogen, —OR¹¹, —NR¹¹R¹²,S(O)₂R¹², —C(O)R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein:

R¹ is H or gem-dimethyl;

R² is H;

R³ is phenyl, pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl,oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl,benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl,benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl,isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, furo[2,3-b]pyrazinyl,imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-a][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl, or3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or non-aromatic heterocycleselected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl,piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl,2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino,1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl, eachof which is optionally and independently substituted 1 to 4 times withsubstituents as defined in R¹⁴;R⁴ is H or F;R⁵ and R⁶ are each independently H, F, Cl, OH, OCH₃, or CH₃;R⁷ is H or F; andR⁸ is H, OH, or F.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein:

R¹ is H or gem-dimethyl;

R² is H;

R³ is 1,2,4-oxadiazol-3-yl, 1,2,3-thiadiazol-4-yl,3,5-dimethylisoxazol-4-yl, 1H-pyrazol-3-yl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl,4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl,pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 2-aminopyridinyl,3-aminopyridinyl, 4-aminopyridinyl, pyridazin-3-yl,6-methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl,6-(difluoromethyl)pyridazin-3-yl,6-(difluoromethoxy)methyl)pyridazin-3-yl, 6-aminopyridazin-3-yl,(6-(hydroxymethyl)pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl,6-aminopyrazin-2-yl, 2-oxopyridin-1(2H)-yl, 2-oxopyrrolidin-1-yl,6-oxo-1,6-dihydropyridazin-3-yl, 6-oxopyridazin-1(6H)-yl,3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl,3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,[1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl,3,3-dimethyl-2-oxoindolin-5-yl,3-methyl-[1,2,4]triazolo[4,3-b]-pyridazinyl,[1,2,4]triazolo[4,3-b]-pyridazinyl, or oxooxazolidin-3-yl;R⁴ is H or F;R⁵ and R⁶ are each independently H, F, Cl, or CH₃;R⁷ is H; andR⁸ is H.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein:

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, C₁-C₆ haloalkyl, or gem-dialkyl of which each alkyl isC₁-C₄;

R² is H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹²,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹R¹⁰;R³ is an aryl selected from the group consisting of phenyl, naphthyl,indanyl, and indenyl, or a heteroaryl selected from the group consistingof pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, furo[2,3-b]pyrazinyl,imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-a][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl, and3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or a non-aromatic heterocycleselected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl,piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl,2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino,1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl;wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionallysubstituted from 1 to 4 times with substituents as defined below in R¹⁴;R⁴ is selected from the group consisting of H, halogen, —NR¹¹R¹²,—NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —SOR¹², —S(O)₂R¹², CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, and wherein each of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from the groupconsisting of C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenyl whichis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰;R⁵ and R⁶ and R⁷ are each independently H or are selected from the groupconsisting of halogen, —OR¹¹, —NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹²,—NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹R¹⁰;R⁸ is H, halogen, or OR¹¹;R⁹ and R¹⁰ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl,or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3times with a substituent selected independently at each occurrencethereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy;or R⁹ and R¹⁰ are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring;R¹¹ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl, or benzyl, wherephenyl or benzyl is optionally substituted 1 to 3 times with halogen,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R¹² is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, where phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;or R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring, with the provisothat only one of R⁹ and R¹⁰ or R¹¹ and R¹² are taken together with thenitrogen to which they are attached to form a piperidine, pyrrolidine,piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;R¹³ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;n is 0, 1, or 2; andR¹⁴ is independently selected at each occurrence from a substituentselected from the group consisting of halogen, —NO₂, —OR¹¹, —NR¹¹R¹²,—NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, where C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from the group consisting of C₁-C₃ alkyl, halogen,Ar, —CN, —OR⁹, and —NR⁹R¹⁰, oran oxide thereof, a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof;with the proviso that when R³ is phenyl or monocyclic aromaticheterocycle (pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl,pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, ortetrazolyl), R¹⁴ cannot be C₁-C₆ alkyl substituted with —NR⁹R¹⁰.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein:

R¹ is gem-dialkyl of which each alkyl is C₁-C₄;

R² is H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹²,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹R¹⁰;R³ is an aryl selected from the group consisting of phenyl, naphthyl,indanyl, and indenyl, or a heteroaryl selected from the group consistingof pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, furo[2,3-b]pyrazinyl,imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-a][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl, and3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or a non-aromatic heterocycleselected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl,piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl,2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino,1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl;wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionallysubstituted from 1 to 4 times with substituents as defined below in R¹⁴;R⁴, R⁵ and R⁶ and R⁷ are each independently H or are selected from thegroup consisting of halogen, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN, —C(O)R¹²,—C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, and wherein each of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from the groupconsisting of C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenyl whichis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰;R⁸ is H, halogen, or OR¹¹;R⁹ and R¹⁰ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl,or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3times with a substituent selected independently at each occurrencethereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy;or R⁹ and R¹⁰ are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring;R¹¹ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl, or benzyl, wherephenyl or benzyl is optionally substituted 1 to 3 times with halogen,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R¹² is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, where phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;or R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring, with the provisothat only one of R⁹ and R¹⁰ or R¹¹ and R¹² are taken together with thenitrogen to which they are attached to form a piperidine, pyrrolidine,piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;R¹³ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;n is 0, 1, or 2; andR¹⁴ is independently selected at each occurrence from a substituentselected from the group consisting of halogen, —NO₂, —OR¹¹, —NR¹¹R¹²,NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, where C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from the group consisting of C₁-C₃ alkyl, halogen,Ar, —CN, —OR⁹, and —NR⁹R¹⁰, oran oxide thereof, a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein:

R¹ is H, C₁-C₄ alkyl, or gem-dialkyl of which each alkyl is C₁-C₄;

R² is H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹²,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹R¹⁰;R³ is [1,2,4]triazolo[1,5-a]pyridine-2-yl,[1,2,4]triazolo[1,5-a]pyridine-5-yl,[1,2,4]triazolo[1,5-a]pyridine-6-yl,[1,2,4]triazolo[1,5-a]pyridine-7-yl, or[1,2,4]triazolo[1,5-a]pyridine-8-yl which is optionally substituted byR¹⁴;R⁴ is H, F, Cl, Me, CN, OR¹¹, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, or C₄-C₇ cycloalkylalkyl, and wherein each of C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from the groupconsisting of C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenyl whichis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰;R⁵, R⁶, and R⁷ are each independently H or are selected from the groupconsisting of halogen, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹²,—NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹, R¹⁰;R⁸ is H, halogen, OR¹¹ or C¹-C⁴ alkyl;R⁹ and R¹⁰ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl,or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3times with a substituent selected independently at each occurrencethereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy;or R⁹ and R¹⁰ are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring;R¹¹ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹³, phenyl, or benzyl, wherephenyl or benzyl is optionally substituted 1 to 3 times with halogen,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R¹² is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl or benzyl, where phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;or R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring, with the provisothat only one of R⁹ and R¹⁰ or R¹¹ and R¹² are taken together with thenitrogen to which they are attached to form a piperidine, pyrrolidine,piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;R¹³ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;n is 0, 1, or 2; and,R¹⁴ is independently selected at each occurrence from a substituentselected from the group consisting of halogen, —NO₂, —OR¹¹, —NR¹¹R¹²,—NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, where C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from the group consisting of C₁-C₃ alkyl, halogen,Ar, —CN, —OR⁹, and —NR⁹R¹⁰, oran oxide thereof, a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein:

R¹ is H, methyl, or gem-dimethyl;

R² is H, F, Cl, CN, Me, CF₃, CF₂H, OMe, OCF₃, OCF₂H, or OH;

R³ is [1,2,4]triazolo[1,5-a]pyridinyl-6-yl which is optionallysubstituted by R¹⁴;

R⁴ is H, F, Cl, CN, Me, CF₃, CF₂H, OMe, OCF₃, OCF₂H, or OH;

R⁵ to R⁷ are independently, H, F, Cl, CN, Me, CF₃, CF₂H, OMe, OCF₃,OCF₂H, or OH; and

R⁸ is H or methyl,

or an oxide thereof, a pharmaceutically acceptable salt thereof, asolvate thereof, or a prodrug thereof.

Another more preferred embodiment of the present invention is thecompound of formula (I) with the proviso that R³ is not[1,2,4]triazolo[1,5-a]pyridin-6-yl. Yet another preferred embodiment ofthe present invention is the compound of formula (I) with the provisothat when R¹, R², R⁴, R⁵, and R⁸ are H and R⁶ and R⁷ are Cl, R³ is not[1,2,4]triazolo[1,5-a]pyridin-6-yl.

In another more preferred embodiment of the present invention, thecompound of formula (I) is a (+)-stereoisomer.

In another more preferred embodiment of the present invention, thecompound of formula (I) is a (−)-stereoisomer.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein the carbon atom designated * is in the Rconfiguration.

Another more preferred embodiment of the present invention is thecompound of formula (I) wherein the carbon atom designated * is in the Sconfiguration.

In another preferred embodiment of the present invention, the compoundof formula (I) is a (S)(+)-stereoisomer.

In yet another preferred embodiment of the present invention, thecompound of formula (I) is a (R)(−)-stereoisomer.

Another preferred embodiment of the present invention is a mixture ofstereoisomeric compounds of formula (I) wherein * is in the S or Rconfiguration.

Within these embodiments, the selection of a particular preferredsubstituent at any one of R¹-R⁸ does not affect the selection of asubstituent at any of the others of R¹-R⁸. That is, preferred compoundsprovided herein have any of the preferred substituents at any of thepositions. For example, as described hereinabove, R¹ is preferably H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, C₁-C₆haloalkyl, or gem-dialkyl of which each alkyl isC₁-C₄; the selection of R¹ as any one of H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₁-C₆ haloalkyl,or gem-dialkyl of which each alkyl is C₁-C₄, does not limit the choiceof R² in particular to any one of H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, or C₄-C₇ cycloalkylalkyl. Rather, for R¹ as any of H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, C₁-C₆ haloalkyl, or gem-dialkyl of which each alkyl isC₁-C₄, R² is any of H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN, —C(O)R¹²,—C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, or C₄-C₇ cycloalkylalkyl.

More preferred compounds of the present invention are described with thefollowing substituents in Table 1, wherein the carbon atom designed * isin the R or S configuration.

TABLE 1 R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ Example H H 6-methylpyridazin-3-yl H HMe H H 1 H H 6-aminopyridazin-3-yl H H F H H 2 H H6-(methylamino)pyridazin-3-yl H H F H H 3 H H6-(trifluoromethyl)pyridazin-3-yl H H Cl H H 4 H H 6-aminopyridazin-3-ylH H Cl H H 5 Me H 6-choropyridazin-3-yl H H Cl H H 6 Me H pyridazin-3-ylH H Cl H H 7 Me H 6-methoxypyridazin-3-yl H H Cl H H 8 gem-dimethyl Hpyridazin-3-yl H Cl Cl H H 9 gem-dimethyl H6-(trifluoromethyl)pyridazin-3-yl H Cl Cl H H 10 H H6-(trifluoromethyl)pyridazin-3-yl H Cl Cl H H 11 H H6-(difluoromethoxy)pyridazin-3-yl H Cl Cl H H 12 gem-dimethyl H6-aminopyridazin-3-yl H Cl Cl H H 13 H H 2-cyanophenyl H Cl Cl H H 14 HH 3-cyanophenyl H Cl Cl H H 15 H H 4-(methylsulfonyl)phenyl H Cl Cl H H16 H H 2-oxopyridin-1(2H)-yl H Cl Cl H H 17 H H 6-oxopyridazin-1(6H)-ylH Cl Cl H H 18 H H pyridin-2-yl F Cl Cl H H 19 H H6-methylpyridazin-3-yl F Cl Cl H H 20 H H 6-methoxypyridazin-3-yl F ClCl H H 21 H H 6-oxo-1,6-dihydropyridazin-3-yl F Cl Cl H H 22 H H3-(methylsulfonyl)phenyl F Cl Cl H H 23 H H 4-carbamoylphenyl H Cl Cl HH 24 H H 3,5-dimethylisoxazol-4-yl H Cl Cl H H 25 H H 4-carbamoylphenylF Cl Cl H H 26 H H 5-aminopyrazin-2-yl H Cl Cl H H 27 H H6-aminopyrazin-2-yl H Cl Cl H H 28 H H 6-(trifluoromethyl)pyridazin-3-ylF Cl Cl H H 29 H H 4-carbamoylphenyl F H Cl H H 30 H H6-(difluoromethoxy)pyridazin-3-yl F Cl Cl H H 31 H H pyrazin-2-yl F ClCl H H 32 H H pyridazin-3-yl H Cl Cl H H 33 H H 6-aminopyridazin-3-yl HCl Cl H H 34 gem-dimethyl H 6-(trifluoromethyl)pyridazin-3-yl H H Cl H H35 H H [1,2,4]triazolo[1,5-a]pyridin-6-yl H Cl Cl H H 36 H H[1,2,4]triazolo[1,5-a]pyridin-6-yl H Cl Cl H H 37 H H[1,2,4]triazolo[1,5-a]pyridin-6-yl H Cl Cl H H 38 H H[1,2,4]triazolo[1,5-a]pyridin-6-yl F Cl Cl H H 39 gem-dimethyl H[1,2,4]triazolo[1,5-a]pyridin-6-yl H Cl Cl H H 40

That is, specific preferred compounds provided herein include, but arenot limited to:

-   4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;-   7-(6-methylpyridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline;-   6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;-   6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine;-   4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   6-(4-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;-   4-(4-chlorophenyl)-7-(6-chloropyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline;-   4-(4-chlorophenyl)-1-methyl-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(4-chlorophenyl)-7-(6-methoxypyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-1,1-dimethyl-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-1,1-dimethyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   6-(4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;-   2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;-   3-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;-   4-(3,4-dichlorophenyl)-7-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline;-   1-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one;-   2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one;-   4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methylpyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   6-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one;-   4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline;-   4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dimethylisoxazole;-   4-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide;-   5-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine;-   6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine;-   4-(3,4-dichlorophenyl)-6-fluoro-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(4-(4-chlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide;-   4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;-   4-(4-chlorophenyl)-1,1-dimethyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;-   7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline;-   7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;-   7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;-   7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-7-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-7-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-7-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;-   4-(3,4-dichlorophenyl)-7-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;-   6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2(3H)-one;    or an oxide thereof, a pharmaceutically acceptable salt thereof, a    solvate thereof, or a prodrug thereof.

Single enantiomers, any mixture of enantiomers, including racemicmixtures, or diastereomers (both separated and as any mixtures) of thecompounds of the present invention are also included within the scope ofthe invention.

The scope of the present invention also encompasses active metabolitesof the present compounds.

The present invention also includes compounds of formula (I), whereinone or more of the atoms, e.g., C or H, are replaced by thecorresponding radioactive isotopes of that atom (e.g., C replaced by ¹⁴Cand H replaced by ³H), or a stable isotope of that atom (e.g., Creplaced by ¹³C or H replaced by ²H). Such compounds have a variety ofpotential uses, e.g., as standards and reagents in determining theability of a potential pharmaceutical to bind to neurotransmitterproteins. In addition, in the case of stable isotopes, such compoundsmay have the potential to favorably modify the biological properties,e.g., pharmacological and/or pharmacokinetic properties, of compounds offormula (I). The details concerning selection of suitable sites forincorporating radioactive isotopes into the compounds are known to thoseskilled in the art.

Another aspect of the present invention is a pharmaceutical compositioncontaining a therapeutically effective amount of the compound of formula(I) and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method of treatinga disorder which is created by or is dependent upon decreasedavailability of serotonin, norepinephrine, or dopamine. The methodinvolves administering to a patient in need of such treatment atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof. The method of the presentinvention is capable of treating subjects afflicted with variousneurological and psychiatric disorders including, without limitation:attention deficit hyperactivity disorder (ADHD), cognition impairment,anxiety disorders, generalized anxiety disorder (GAD), panic disorder,bipolar disorder or manic depression or manic-depressive disorder,obsessive compulsive disorder (OCD), posttraumatic stress disorder(PTSD), acute stress disorder, social phobia, simple phobias,pre-menstrual dysphoric disorder (PMDD), social anxiety disorder (SAD),major depressive disorder (MDD), postnatal depression, dysthymia,depression associated with Alzheimer's disease, Parkinson's disease, orpsychosis, supranuclear palsy, eating disorders, obesity, anorexianervosa, bulimia nervosa, binge eating disorder, diabetes, ischemicdiseases, pain, substance abuse disorders, chemical dependencies,nicotine addiction, cocaine addiction, amphetamine addiction, alcoholaddiction, Lesch-Nyhan syndrome, neurodegenerative diseases, Parkinson'sdisease, late luteal phase syndrome or narcolepsy, psychiatric symptoms,anger, rejection sensitivity, movement disorders, extrapyramidalsyndrome, Tic disorders, restless leg syndrome (RLS), tardivedyskinesia, supranuclear palsy, sleep related eating disorder (SRED),night eating syndrome (NES), stress urinary incontinence (SUI),migraine, neuropathic pain, diabetic neuropathy, lower back pain,fibromyalgia syndrome (FS), osteoarthritis pain, arthritis pain, chronicfatigue syndrome (CFS), sexual dysfunction, premature ejaculation, maleimpotence, thermoregulatory disorders (e.g., hot flashes associated withmenopause), and irritable bowel syndrome (IBS).

The compounds provided herein are particularly useful in the treatmentof these and other disorders due, at least in part, to their ability toselectively bind to the transporter proteins for certain neurochemicalswith a greater affinity than to the transporter proteins for otherneurochemicals.

In another embodiment of the present invention, the above method furtherinvolves administering a therapeutically effective amount of a serotonin1A receptor antagonist or a pharmaceutically acceptable salt thereof.Suitable serotonin 1A receptor antagonists include WAY 100135 andspiperone. WAY 100135(N-(t-butyl)-3-[a-(2-methoxyphenyl)piperazin-1-yl]-2 phenylpropanamide)is disclosed as having an affinity for the serotonin 1A receptor in U.S.Pat. No. 4,988,814 to Abou-Gharbia et al., which is hereby incorporatedby reference in its entirety. Also, Cliffe et al., J Med Chem 36:1509-10(1993), which is hereby incorporated by reference in its entirety,showed that the compound is a serotonin 1A antagonist. Spiperone(8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one)is a well-known compound and is disclosed in U.S. Pat. Nos. 3,155,669and 3,155,670, which are hereby incorporated by reference in theirentirety. The activity of spiperone as a serotonin 1A antagonist isdescribed in Middlemiss et al., Neurosc and Biobehav Rev. 16:75-82(1992), which is hereby incorporated by reference in its entirety.

In another embodiment of the present invention, the above method furtherinvolves administering a therapeutically effective amount of a selectiveneurokinin-1 receptor antagonist or pharmaceutically acceptable saltthereof. Neurokinin-1 receptor antagonists that can be used incombination with the compound of formula (I), in the present inventionare fully described, for example, in U.S. Pat. Nos. 5,373,003,5,387,595, 5,459,270, 5,494,926, 5,162,339, 5,232,929, 5,242,930,5,496,833, and 5,637,699; PCT International Patent Publication Nos. WO90/05525, 90/05729, 94/02461, 94/02595, 94/03429,94/03445, 94/04494,94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168,94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320,94/19323, 94/20500, 91/09844, 91/18899, 92/01688, 92/06079,92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569,93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099,93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155,93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/26735, 94/26740,94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908,95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124,95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338,95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203,96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661,96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489,97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206,97/19084, 97/19942, 97/21702, and 97/49710; and in U.K. PatentApplication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774,2 292 144, 2 293168, 2 293 169, and 2 302 689; European PatentPublication Nos. EP 0 360 390, 0 517 589, 0 520 555, 0 522 808, 0 528495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0585 913, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693489, 0 694 535, 0 699 655, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893, which are hereby incorporated by reference in theirentirety. The preparations of such compounds are fully described in theaforementioned patents and publications.

In another embodiment of the present invention, the above method furtherinvolves administering a therapeutically effective amount of anorepinephrine precursor or a pharmaceutically acceptable salt thereof.Suitable norepinephrine precursors include L-tyrosine andL-phenylalanine.

Another embodiment of the present invention is a method of inhibitingsynaptic norepinephrine uptake in a patient in need thereof. The methodinvolves administering a therapeutically effective inhibitory amount ofa compound of formula (I).

Another embodiment of the present invention is a method of inhibitingsynaptic serotonin uptake in a patient in need thereof. The methodinvolves administering a therapeutically effective inhibitory amount ofa compound of formula (I).

Another embodiment of the present invention is a method of inhibitingsynaptic dopamine uptake in a patient in need thereof. The methodinvolves administering a therapeutically effective inhibitory amount ofa compound of formula (I).

Another embodiment of the present invention is a therapeutic methoddescribed herein, where the (+)-stereoisomer of the compound of formula(I) is employed.

Another embodiment of the present invention is a therapeutic methoddescribed herein, where the (−)-stereoisomer of the compound of formula(I) is employed.

Another embodiment of the present invention is a kit comprising acompound of formula (I), and at least one compound selected from thegroup consisting of: a serotonin 1A receptor antagonist compound, aselective neurokinin-1 receptor antagonist compound, and anorepinephrine precursor compound.

Another embodiment of the present invention relates to a method oftreating a disorder referred to in the above-mentioned embodiments in apatient in need thereof. The method involves inhibiting synapticserotonin and norepinephrine uptake by administering a therapeuticallyeffective inhibitory amount of the compound of formula (I), whichfunctions as both a dual acting serotonin and norepinephrine uptakeinhibitor.

Another embodiment of the present invention relates to a method oftreating a disorder referred to in the above-mentioned embodiments in apatient in need thereof. The method involves inhibiting synapticserotonin and dopamine uptake by administering a therapeuticallyeffective inhibitory amount of the compound of formula (I), whichfunctions as both a dual acting serotonin and dopamine uptake inhibitor.

Another embodiment of the present invention relates to a method oftreating a disorder referred to in the above-mentioned embodiments in apatient in need thereof. The method involves inhibiting synapticdopamine and norepinephrine uptake by administering a therapeuticallyeffective inhibitory amount of the compound of formula (I), whichfunctions as both a dual acting dopamine and norepinephrine uptakeinhibitor.

Another embodiment of the present invention relates to a method oftreating a disorder referred to in the above-mentioned embodiments in apatient in need thereof. The method involves inhibiting synapticnorepinephrine, dopamine, and serotonin uptake by administering atherapeutically effective inhibitory amount of the compound of formula(I), which functions as a triple acting norepinephrine, dopamine, andserotonin uptake inhibitor.

Another embodiment of the present invention relates to a method forinhibiting serotonin uptake in mammals. The method involvesadministering to a mammal requiring increased neurotransmission ofserotonin a pharmaceutically effective amount of the compound of formula(I).

Another embodiment of the present invention relates to a method forinhibiting dopamine uptake in mammals. The method involves administeringto a mammal requiring increased neurotransmission of dopamine apharmaceutically effective amount of the compound of formula (I).

Another embodiment of the present invention relates to a method forinhibiting norepinephrine uptake in mammals. The method involvesadministering to a mammal requiring increased neurotransmission ofnorepinephrine a pharmaceutically effective amount of the compound offormula (I).

Another embodiment of the present invention relates to a method ofsuppressing the desire of humans to smoke. The method involvesadministering to a human in need of such suppression an effective dose,to relieve the desire to smoke, of the compound of formula (I).

Another embodiment of the present invention relates to a method ofsuppressing the desire of humans to consume alcohol. The method involvesadministering to a human in need of such suppression an effective dose,to relieve the desire to consume alcohol, of the compound of formula(I).

Another embodiment of the present invention relates to a process forpreparation of a product compound of Formula (I). This process comprisestreating a first intermediate compound of Formula (II):

with an acid under conditions effective to produce the product compound.

Suitable acids include, but are not limited to, sulfuric acid,methansulfonic acid, phorphoric acid, and L-tartaric acid.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Compounds according to the invention, for example, starting materials,intermediates, or products, are prepared as described herein or by theapplication or adaptation of known methods, by which is meant methodsused heretofore or described in the literature.

Compounds useful according to the invention may be prepared by theapplication or adaptation of known methods, by which is meant methodsused heretofore or described in the literature, for example, thosedescribed by Larock, Comprehensive Organic Transformations, Wiley-VCHpublishers, New York (1989), which is hereby incorporated by referencein its entirety.

A compound of formula (I) including a group containing one or morenitrogen ring atoms, may be converted to the corresponding compoundwherein one or more nitrogen ring atom of the group is oxidized to anN-oxide, preferably by reacting with a peracid, for example peraceticacid in acetic acid or m-chloroperoxybenzoic acid in an inert solventsuch as dichloromethane, at a temperature from about room temperature toreflux, preferably at elevated temperature.

In the reactions described hereinafter, it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio, orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice (e.g., Wuts etal., Protective Groups in Organic Chemistry (4^(th) Edition), Wiley(2006), and McOmie, Protective Groups in Organic Chemistry, Plenum Press(1973), which are hereby incorporated by reference in their entirety).

The novel tetrahydroisoquinoline reuptake inhibitors of Formula (I) ofthis invention can be prepared by the general scheme outlined below(Scheme 1). The methyl-substituted N-benzyl amines of Formula (II) maybe purchased from commercial sources, or alternatively, obtained from asimple reductive amination protocol under a wide variety of conditionsfamiliar to one skilled in the art of organic synthesis (Larock,Comprehensive Organic Transformations, Wiley-VCH publishers, New York,(1989), which is hereby incorporated by reference in its entirety). Inaddition, one skilled in the art will be familiar with other methods ofbenzylamine synthesis described in Larock, Comprehensive OrganicTransformations, Wiley-VCH publishers, New York, (1989).

Treatment of amines of Formula (II) with halides (bromides or chlorides)of Formula (III) generates the alkylation products of Formula (IV). Thealkylation reactions may be run under a wide variety of conditionsfamiliar to one skilled in the art of organic synthesis. Typicalsolvents include acetonitrile, toluene, diethyl ether, tetrahydrofuran,dimethylsulfoxide, dimethylformamide, methylene chloride, and loweralkyl alcohols including ethanol. The reactions may be successfully runat temperatures ranging from 0° C. up to the boiling point of thesolvent employed. Reaction progress is conventionally monitored bystandard chromatographic and spectroscopic methods. The alkylationreaction is optionally run with the addition of a non-nucleophilicorganic base such as, but not limited to, pyridine, triethylamine, anddiisopropyl ethylamine.

The aforementioned intermediate of formula (III) may be purchased fromcommercial sources or prepared via treatment of an optionallysubstituted ketone of Formula (IX)

with common brominating agents such as, but not limited to, bromine,NBS, or tetrabutylammonium tribromide which readily affords the desiredbromoacetophenones of Formula (III). These reactions are optimallyconducted in acetic acid or methylene chloride with methanol used as aco-solvent for the tribromide reagent with reaction temperatures at orbelow room temperature. Another embodiment of this methodology wouldinclude the use of chloroacetophenone compounds of Formula (III).

The ketones of Formula (IX) are available from commercial sources or areconveniently obtained via several well known methods, including thetreatment of the corresponding aromatic carboxylic acid intermediateswith two stoichiometric equivalents of methyllithium (Jorgenson, OrganicReactions, 18:1 (1970), which is hereby incorporated by reference in itsentirety). Alternatively, one may treat the corresponding aromaticaldehydes with an alkyl-Grignard (for example, MeMgBr) or alkyl-lithium(for example, MeLi) nucleophile followed by oxidation to thecorrespondent ketones under a wide variety of conditions familiar to oneskilled in the art of organic synthesis (see, e.g., Larock,Comprehensive Organic Transformations, Wiley-VCH publishers (1989),which is hereby incorporated by reference in its entirety).

Reductions of compounds of Formula (IV) to the secondary alcohols ofFormula (V) proceeds with many reducing agents including, for example,sodium borohydride, lithium borohydride, borane, diisobutylaluminumhydride, and lithium aluminum hydride. The reductions are carried outfor a period of time between 1 hour to 3 days at room temperature orelevated temperature up to the reflux point of the solvent employed. Ifborane is used, it may be employed as a complex for example, but notlimited to, borane-methyl sulfide complex, borane-piperidine complex, orborane-tetrahydrofuran complex. One skilled in the art will understandthe optimal combination of reducing agents and reaction conditionsneeded or may seek guidance from the text of Larock, ComprehensiveOrganic Transformations, Wiley-VCH publishers (1989), which is herebyincorporated by reference in its entirety.

Compounds of Formula (V) may be cyclized to the tetrahydroisoquinolinecompounds of Formula (VI) of this invention by the treatment with astrong acid. Suitable acids include, but are not limited to,concentrated sulfuric acid, polyphosphoric acid, methanesulfonic acid,trifluoroacetic acid, and Eaton's reagent(Phosphorpentoxid/methanesulfonic acid). The reactions are run neat orin the optional presence of a co-solvent such as, for example, methylenechloride or 1,2-dichloroethane. The cyclizations may be conducted attemperatures ranging from 0° C. up to the reflux point of the solventemployed. One skilled in the art of heterocyclic chemistry will readilyunderstand these conditions or may consult the teachings of Mondeshka,Il Farmaco, 49:475-480 (1994) and Venkov, Synthesis, 253-255 (1990),which are hereby incorporated by reference in their entirety.Cyclizations may also be effected by treatment of compounds of Formula(V) with strong Lewis acids, such as aluminum trichloride typically inhalogenated solvents such as methylene chloride. One skilled in the artwill be familiar with the precedent taught by Kaiser, J Med Chem,27:28-35 (1984) and Wyrick, J Med Chem, 24:1013-1015 (1981), which arehereby incorporated by reference in their entirety.

Compounds of Formula (VI, Y═OMe) may be converted to compounds ofFormula (VI, Y═OH) by a demethylation procedure such as, but not limitedto heating to reflux in aqueous HBr with or without an organic solventsuch as acetic acid, or treatment with BBr₃ in methylene chloride at lowtemperature. One skilled in the art will understand the optimalcombination of demethylation agents and reaction conditions needed ormay seek guidance from the text of Wuts et al., Protective Groups inOrganic Chemistry (4^(th) Edition), published by Wiley (2006), which ishereby incorporated by reference in its entirety.

Compounds of Formula (VI, Y═OH) may be converted to compounds of formula(VI; OSO₂CF₃) by reacting with a triflating reagent such astrifluoromethanesulfonic anhydride in the presence of a base such aspyridine in a halogenated solvent such as methylene chloride. Compoundsof formula (VII) of this invention may be prepared by treatment ofcompounds of Formula (VI; Y═Br, OSO₂CF₃) with aryl or heteroaryl boronicacids or aryl or heteroaryl boronic acid esters with formula Z—R³ whereZ is equivalent to B(OH)₂ or B(OR^(a))(OR^(b)) (where R^(a) and R^(b)are lower alkyl, i.e., C₁-C₆ alkyl, or taken together, R^(a) and R^(b)are lower alkylene, i.e., C₂-C₁₂ alkylene) in the presence of a metalcatalyst with or without a base in an inert solvent to givetetrahydroisoquinoline compounds of Formula (VII). Metal catalystsinclude, but are not limited to, salts or phosphine complexes of Cu, Pd,or Ni (e.g., Cu(OAc)₂, PdCl₂ (PPh₃)₂, and NiCl₂ (PPh₃)₂). Bases mayinclude, but are not limited to, alkaline earth metal carbonates,alkaline earth metal bicarbonates, alkaline earth metal hydroxides,alkali metal carbonates, alkali metal bicarbonates, alkali metalhydroxides, alkali metal hydrides (preferably sodium hydride), alkalimetal alkoxides (preferably sodium methoxide or sodium ethoxide),alkaline earth metal hydrides, alkali metal dialkylamides (preferablylithium diisopropylamide), alkali metal bis(trialkylsilyl)amides(preferably sodium bis(trimethylsilyl)amide), trialkyl amines(preferably diisopropylethylamine or triethylamine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto acetonitrile, dialkyl ethers (preferably diethyl ether), cyclicethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylacetamides (preferably dimethylacetamide),N,N-dialkylformamides (preferably dimethylformamide), dialkylsulfoxides(preferably dimethylsulfoxide), aromatic hydrocarbons (preferablybenzene or toluene) or haloalkanes (preferably methylene chloride).Preferred reaction temperatures range from room temperature up to theboiling point of the solvent employed. The reactions may be run inconventional glassware or in one of many commercially available parallelsynthesizer units. Non-commercially available boronic acids or boronicacid esters may be obtained from the corresponding optionallysubstituted aryl halide as described by Gao, Tetrahedron, 50:979-988(1994), which is hereby incorporated by reference in its entirety. Itwill also be appreciated by one skilled in the art that compounds ofFormula (VI, Y═Br, OSO₂CF₃) may be converted to the correspondingboronic acids or boronate esters and subsequently treated with the arylor heteroaryl halides or triflate R³—X (X═Cl, Br, I, OSO₂CF₃) indiscreet steps or in tandem as taught by Baudoin, J Org Chem,67:1199-1207 (2002), which is hereby incorporated in its entirety.

Compounds of formula (I) can be obtained by an N-demethylation proceduretaught by Koreeda and Luengo, J. Org. Chem. 49: 2081-2082 (1984), whichis hereby incorporated in its entirety. Thus compounds of formula (VII)may be treated with 1-chloroethyl chloroformate in the presence of aproton scavenger such as, but not limited toN¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (known as “protonsponge”) in a halogenated solvent such as 1,2-dichloroethane ormethylene chloride at temperatures ranging from 0° C. up to the boilingpoint of the solvent employed. The resulting carbamate intermediate maybe heated in a low alkyl alcohol solvent such as methanol to give thetarget compounds of formula (I).

Alternatively, compounds of formula (VI, Y═OMe, OSO₂CF₃, Br,B(OR^(a))(OR^(b))) may be N-demethylated via aforementioned methods toyield compounds of formula (VIII), which then may be converted tocompounds of formula (I) via aforementioned methods. The protection ofthe nitrogen of the tetrahydroisoquinoline of formula (VIII) may beneeded. Examples of typical protecting groups are Boc, F-Moc, and2-nitrobenzenesulfonyl.

An alternative synthesis of compounds of formula (I) is to start withthe compounds of formula (X), below.

Compounds of formula (X) may be purchased from commercial sources, ormade following the teaching in Larock, Comprehensive OrganicTransformations, Wiley-VCH publishers, New York, (1989), which isfamiliar to one skilled in the art of organic synthesis and is herebyincorporated by reference in its entirety. Compounds of formula (X) maybe converted to compounds of formula (I) via methods similar to the onesdescribed earlier for the transformation of compounds of formula (II) tocompounds of formula (VII). Compounds of Formula (IV) may be treatedwith a C₁-C₄ alkyl lithium reagent or a C₁-C₄ alkyl Grignard reagent.The resulting tertiary alcohols may then be converted to compounds ofFormula (VI), wherein R⁸ is the corresponding C₁-C₄ alkyl, then tocompounds of Formula (I), wherein R⁸ is the corresponding C₁-C₄ alkyl,using the aforementioned methods.

Another method of preparing compounds in this invention is exemplifiedby the alternative synthesis of Example 2, as depicted in Scheme 2.

Suzuki coupling of 3-formylphenylboronic acid and6-bromo-[1,2,4]triazolo[1,5-a]pyridine gave3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde. This aldehydeunderwent a reductive amination to gave2-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzylamino)-1-(3,4-dichlorophenyl)ethanol,which was then subjected to sulfuric acid mediated cyclization toprovide7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline.

A synthetic route of preparing L-tartrate salts of the present inventionis depicted in Scheme 3.

Compounds of formula (I) may be obtained in enantiomerically enriched(R) and (S) form by crystallization with chiral salts as well known toone skilled in the art, or alternatively, may be isolated through chiralHPLC employing commercially available chiral columns.

It will be appreciated that compounds according to the present inventionmay contain asymmetric centers. These asymmetric centers mayindependently be in either the R or S configuration and such compoundsare able to rotate a plane of polarized light in a polarimeter. If saidplane of polarized light is caused by the compound to rotate in acounterclockwise direction, the compound is said to be the (−)stereoisomer of the compound. If said plane of polarized light is causedby the compound to rotate in a clockwise direction, the compound is saidto be the (+) stereoisomer of the compound. It will be apparent to thoseskilled in the art that certain compounds useful according to theinvention may also exhibit geometrical isomerism. It is to be understoodthat the present invention includes individual geometrical isomers andstereoisomers and mixtures thereof, including racemic mixtures, ofcompounds of formula (I) hereinabove. Such isomers can be separated fromtheir mixtures, by the application or adaptation of known methods, forexample chromatographic techniques and recrystallization techniques, orthey are separately prepared from the appropriate isomers of theirintermediates.

Radiolabelled compounds of the invention are synthesized by a number oftechniques well known to those of ordinary skill in the art, e.g., byusing starting materials incorporating therein one or moreradioisotopes. Compounds of the present invention where a stableradioisotope, such as carbon-14, tritium, iodine-121, or anotherradioisotope, has been introduced synthetically are useful diagnosticagents for identifying areas of the brain or central nervous system thatmay be affected by disorders where norepinephrine, dopamine, orserotonin transporters and their uptake mechanism are implicated.

The present invention provides compositions containing the compoundsdescribed herein, including, in particular, pharmaceutical compositionscomprising therapeutically effective amounts of the compounds andpharmaceutically acceptable carriers.

It is a further object of the present invention to provide kits having aplurality of active ingredients (with or without carrier) which,together, may be effectively utilized for carrying out the novelcombination therapies of the invention.

It is another object of the invention to provide a novel pharmaceuticalcomposition which is effective, in and of itself, for utilization in abeneficial combination therapy because it includes a plurality of activeingredients which may be utilized in accordance with the invention.

The present invention also provides kits or single packages combiningtwo or more active ingredients useful in treating the disease. A kit mayprovide (alone or in combination with a pharmaceutically acceptablediluent or carrier) the compounds of formula (I) and the additionalactive ingredient (alone or in combination with diluent or carrier)selected from a serotonin 1A receptor antagonist, a selectiveneurokinin-1 receptor antagonist, and a norepinephrine precursor.

In practice, the compounds of the present invention may generally beadministered parenterally, intravenously, subcutaneously,intramuscularly, colonically, nasally, intraperitoneally, rectally, ororally.

The products according to the present invention may be presented informs permitting administration by the most suitable route and theinvention also relates to pharmaceutical compositions containing atleast one product according to the invention which are suitable for usein human or veterinary medicine. These compositions may be preparedaccording to the customary methods, using one or more pharmaceuticallyacceptable adjuvants or excipients. The adjuvants comprise, inter alia,diluents, sterile aqueous media, and the various non-toxic organicsolvents. The compositions may be presented in the form of tablets,pills, granules, powders, aqueous solutions or suspensions, injectablesolutions, elixirs or syrups, and can contain one or more agents chosenfrom the group comprising sweeteners, flavorings, colorings, orstabilizers in order to obtain pharmaceutically acceptable preparations.

The choice of vehicle and the content of active substance in the vehicleare generally determined in accordance with the solubility and chemicalproperties of the product, the particular mode of administration and theprovisions to be observed in pharmaceutical practice. For example,excipients such as lactose, sodium citrate, calcium carbonate, dicalciumphosphate and disintegrating agents such as starch, alginic acids andcertain complex silicates combined with lubricants such as magnesiumstearate, sodium lauryl sulfate, and talc may be used for preparingtablets. To prepare a capsule, it is advantageous to use lactose andhigh molecular weight polyethylene glycols. When aqueous suspensions areused they can contain emulsifying agents or agents which facilitatesuspension. Diluents such as sucrose, ethanol, polyethylene glycol,propylene glycol, glycerol, and chloroform or mixtures thereof may alsobe used.

For parenteral administration, emulsions, suspensions, or solutions ofthe products according to the invention in vegetable oil, for examplesesame oil, groundnut oil, or olive oil, or aqueous-organic solutionssuch as water and propylene glycol, injectable organic esters such asethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride, and that they are sterilized by heating, irradiation, ormicrofiltration.

Suitable compositions containing the compounds of the present inventionmay be prepared by conventional means. For example, compounds of thepresent invention may be dissolved or suspended in a suitable carrierfor use in a nebulizer or a suspension or solution aerosol, or may beabsorbed or adsorbed onto a suitable solid carrier for use in a drypowder inhaler.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing at least onecompound of formula (I).

The percentage of active ingredient in the compositions of the presentinvention may be varied, it being necessary that it should constitute aproportion such that a suitable dosage shall be obtained. Obviously,several unit dosage forms may be administered at about the same time.The dose employed will be determined by the physician, and depends uponthe desired therapeutic effect, the route of administration and theduration of the treatment, and the condition of the patient. In theadult, the doses are generally from about 0.01 to about 100 mg/kg bodyweight, preferably about 0.01 to about 10 mg/kg body weight per day byinhalation, from about 0.01 to about 100 mg/kg body weight, preferably0.1 to 70 mg/kg body weight, more especially 0.1 to 10 mg/kg body weightper day by oral administration, and from about 0.01 to about 50 mg/kgbody weight, preferably 0.01 to 10 mg/kg body weight per day byintravenous administration. In each particular case, the doses will bedetermined in accordance with the factors distinctive to the subject tobe treated, such as age, weight, general state of health, and othercharacteristics which can influence the efficacy of the medicinalproduct.

The products according to the present invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

The present invention provides compounds which inhibit synapticnorepinephrine, dopamine, and serotonin uptake and are, therefore,believed to be useful in treating a disorder which is created by or isdependent upon decreased availability of serotonin, norepinephrine, ordopamine. Although the compounds of formula (I) inhibit synapticnorepinephrine, dopamine, and serotonin uptake, in any individualcompound, these inhibitory effects may be manifested at the same orvastly different concentrations or doses. As a result, some compounds offormula (I) are useful in treating such a disorder at doses at whichsynaptic norepinephrine uptake may be substantially inhibited but atwhich synaptic serotonin uptake or dopamine uptake is not substantiallyinhibited, or vice versa. Also, some compounds of formula (I) are usefulin treating such a disorder at doses at which synaptic dopamine uptakemay be substantially inhibited but at which synaptic norepinephrine orserotonin uptake is not substantially inhibited, or vice versa. And,conversely, some compounds of formula (I) are useful in treating such adisorder at doses at which synaptic serotonin uptake may besubstantially inhibited but at which synaptic norepinephrine or dopamineuptake is not substantially inhibited, or vice versa. Other compounds offormula (I) are useful in treating such a disorder at doses at whichsynaptic norepinephrine, dopamine, and serotonin uptake aresubstantially inhibited.

The present invention provides compounds where the inhibitory effects onserotonin and norepinephrine uptake occurs at similar or even the sameconcentrations of these compounds, while the effects on inhibition ofdopamine uptake occurs at vastly different concentrations or doses. As aresult, some compounds of formula (I) are useful in treating such adisorder at doses at which synaptic serotonin and norepinephrine uptakemay be substantially inhibited but at which synaptic dopamine uptake isnot substantially inhibited, or vice versa.

The present invention provides compounds where the inhibitory effects onserotonin and dopamine uptake occurs at similar or even the sameconcentrations of these compounds while the effects on inhibition ofnorepinephrine uptake occurs at vastly different concentrations ordoses. As a result, some compounds of formula (I) are useful in treatingsuch a disorder at doses at which synaptic serotonin and dopamine uptakemay be substantially inhibited but at which synaptic norepinephrineuptake is not substantially inhibited, or vice versa.

The present invention provides compounds where the inhibitory effects onnorepinephrine and dopamine uptake occurs at similar or even the sameconcentrations of these compounds while the effects on inhibition ofdopamine uptake occurs at vastly different concentrations or doses. As aresult, some compounds of formula (I) are useful in treating such adisorder at doses at which synaptic norepinephrine and dopamine uptakemay be substantially inhibited but at which synaptic serotonin uptake isnot substantially inhibited, or vice versa.

The present invention provides compounds where the inhibitory effects onnorepinephrine, dopamine, and serotonin uptake occur at similar or eventhe same concentration. As a result, some compounds of formula (I) areuseful in treating such a disorder at doses at which synapticnorepinephrine, dopamine, and serotonin uptake may all be substantiallyinhibited.

The concentrations or doses at which a test compound inhibits synapticnorepinephrine, dopamine, and serotonin uptake is readily determined bythe use of standard assay and techniques well known and appreciated byone of ordinary skill in the art. For example, the degree of inhibitionat a particular dose in rats can be determined by the method of Dudley,J Pharmacol Exp Ther, 217:834-840 (1981), which is hereby incorporatedby reference in its entirety.

The therapeutically effective inhibitory dose is one that is effectivein substantially inhibiting synaptic norepinephrine uptake, synapticdopamine uptake, or synaptic serotonin uptake or inhibiting the synapticuptake of two or more of norepinephrine, dopamine, and serotonin uptake.The therapeutically effective inhibitory dose can be readily determinedby those skilled in the art by using conventional range findingtechniques and analogous results obtained in the test systems describedabove.

Compounds of this invention provide a particularly beneficialtherapeutic index relative to other compounds available for thetreatment of similar disorders. Without intending to be limited bytheory, it is believed that this is due, at least in part, to some ofthe compounds having higher binding affinities for one or two of theneurotransmitter transporters, e.g., selectivity towards thenorepinephrine transporter protein (“NET”) over the transporters forother neurochemicals, e.g., the dopamine transporter protein (“DAT”) andthe serotonin transporter protein (“SERT”).

Other compounds of the present invention may demonstrate selectivitytowards the SERT over the transporters for other neurochemicals, e.g.,the DAT and the NET.

Still other compounds of the present invention may demonstrateselectivity towards the DAT over the transporters for otherneurochemicals, e.g., the SERT and the NET.

Yet other compounds of the present invention may demonstrate selectivitytowards the NET over the transporters for other neurochemicals, e.g.,the SERT and the DAT.

Other compounds of the present invention may demonstrate selectivitytowards the SERT and the NET over the transporter for otherneurochemical, e.g., the DAT.

Still other compounds of the present invention may demonstrateselectivity towards the SERT and the DAT over the transporter for otherneurochemical, e.g., the NET.

Still other compounds of the present invention may demonstrateselectivity towards the NET and the DAT over the transporter for otherneurochemical, e.g., the SERT.

Finally other compounds possess nearly identical affinity towards theNET, the DAT, and the SERT.

Binding affinities are demonstrated by a number of means well known toordinarily skilled artisans, including, without limitation, thosedescribed in the Examples section hereinbelow. Briefly, for example,protein-containing extracts from cells, e.g., HEK293E cells, expressingthe transporter proteins are incubated with radiolabelled ligands forthe proteins. The binding of the radioligands to the proteins isreversible in the presence of other protein ligands, e.g., the compoundsof the present invention; said reversibility, as described below,provides a means of measuring the compounds' binding affinities for theproteins (IC₅₀ or Ki). A higher IC₅₀/Ki value for a compound isindicative that the compound has less binding affinity for a proteinthan is so for a compound with a lower IC₅₀/Ki; conversely, lowerIC₅₀/Ki values are indicative of greater binding affinities.

Accordingly, the difference in compound selectivity for proteins isindicated by a lower IC₅₀/Ki for the protein for which the compound ismore selective, and a higher IC₅₀/Ki for the protein for which thecompound is less selective. Thus, the higher the ratio in IC₅₀/Ki valuesof a compound for protein A over protein B, the greater is thecompounds' selectivity for the latter over the former (the former havinga higher IC₅₀/Ki and the latter a lower IC₅₀/Ki for that compound).Compounds provided herein possess a wide range of selectivity profilesfor the norepinephrine, dopamine, and serotonin transporters asreflected by the ratios of the experimentally determined IC₅₀/Ki values.

Selected compounds (“mono action transporter reuptake inhibitors”) ofthe present invention have potent binding affinity for each of thebiogenic amine transporters NET, DAT, or SERT. For example, selectedcompounds of the present invention possess potent (NET IC₅₀/Ki<200 nM)and selective binding affinity for NET. Other selected compounds of thepresent invention possess potent (SERT IC₅₀/Ki<200 nM) and selectivebinding affinity for SERT. Other selected compounds of the presentinvention possess potent (DAT IC₅₀/Ki<200 nM) and selective bindingaffinity for DAT.

Selected compounds (“dual action transporter reuptake inhibitors”) ofthe present invention have potent binding affinity for two of thebiogenic amine transporters, NET, DAT or SERT. For example, selectedcompounds of the present invention possess potent (NET & SERT IC₅₀/Kivalues<200 nM) and selective binding affinity for NET and SERT. Otherselected compounds of the present invention possess potent (NET & DATIC₅₀/Ki values<200 nM) and selective binding affinity for NET and DAT.Other selected compounds of this invention possess potent (DAT & SERTIC₅₀/Ki values<200 nM) and selective binding affinity for DAT and SERT.

Selected compounds (“triple action transporter reuptake inhibitors”) ofthe present invention have potent binding affinity simultaneously forall three of the biogenic amine transporters, NET, DAT, or SERT. Forexample, selected compounds of this invention possess potent (NET, DAT,& SERT IC₅₀/Ki values<200 nM) binding affinity for NET, DAT, and SERT.

The in vivo affinity of the compounds to the three transporter proteins,SERT, DAT, and NET are demonstrated by means well known to those ofordinary skill in the art, including, without limitation, thosedescribed in the Examples section below.

Accordingly, the difference in compound selectivity in vivo for proteinis indicated by a higher percent occupancy value (or percent inhibitionof the [³H] ligand compound used in the Examples section) at thetransporter protein for which the compound is more selective, and alower percent occupancy (or percent inhibition of the ³[H] ligandcompound used in the Examples section) for the protein for which thecompound is less selective. Compounds provided herein possess a widerange of selectivity profiles for the norepinephrine, dopamine, andserotonin transporters as reflected by experimentally determined percentoccupancy values.

Selected compounds of the present invention, when administrated at apharmaceutically feasible dose via means such as, but not limited to,oral, intravenous, subcutaneous, intraperitoneal and intramuscular, havestatistically significant percent occupancy value(s) at one, two or allof the biogenic amine transporters NET, DAT, or SERT.

Selected compounds of the present invention, when administrated at apharmaceutically feasible dose via means such as, but not limited to,oral, intravenous, subcutaneous, intraperitoneal and intramuscular, have10%-100% occupancy value(s) at one, two or all of the biogenic aminetransporters NET, DAT, or SERT. In a preferred embodiment, compounds ofthe present invention have 40%-100% occupancy value(s) at one, two, orall of the biogenic amine transporters NET, DAT, or SERT.

EXAMPLES Example 1 Preparation of7-(6-methylpridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroquinoline,L-tartrate Salt

Step A: To a solution of (3-bromo-benzyl)-methyl-amine (3.0 g, 15.0mmol) in methylene chloride (60 mL) was added diisopropylethylamine (5.2mL, 30.0 mmol). The reaction mixture was cooled to 0° C. and treatedwith 2-bromo-1-p-tolyl-ethanone (3.19 g, 15.0 mmol) portionwise over aperiod of 10 minutes. The reaction mixture was warmed to roomtemperature and stirred for 4 hours. The reaction mixture was washedwith water (3×), dried over sodium sulfate, filtered, and the solventwas evaporated to afford2-((3-bromobenzyl)(methyl)amino)-1-p-tolylethanone (4.89 g, 98%) as aviscous, orange oil: ¹H NMR (CDCl₃, 500 MHz) δ 7.85 (d, J=8.2 Hz, 2H),7.51 (br s, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.28-7.23 (m, 3H), 7.17 (t,J=7.8 Hz, 1H), 3.78 (s, 2H), 3.63 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H).

Step B: Sodium borohydride (646 mg, 17.1 mmol) was added over a periodof 10 minutes to an ice-cooled solution of the product from Step A (4.89g, 15.0 mmol) in methanol (85 mL). The reaction mixture was allowed towarm to room temperature and continued to stir for an additional 2hours. The solvent was removed under reduced pressure and the residuewas diluted with water and extracted with methylene chloride (3×). Thecombined extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo to provide2-((3-bromobenzyl)(methyl)amino)-1-p-tolylethanol (4.58 g, 93%) as anorange oil: ¹H NMR (300 MHz, CDCl₃) δ 7.45 (s, 1H), 7.40 (d, J=5.8 Hz,1H), 7.25-7.13 (m, 6H), 4.72 (dd, J=10.0, 3.7 Hz, 1H), 3.86 (br s, 1H),3.68 (d, J=13.4 Hz, 1H), 3.49 (d, J=13.2 Hz, 1H), 2.62-2.47 (m, 2H),2.33 (s, 3H), 2.30 (s, 3H).

Step C: Methane sulfonic acid (30 mL, 480 mmol) was added dropwise viaaddition funnel to a mixture of the product from Step B (4.58 g, 8.57mmol) in 1,2-dichloroethane (80 mL) at 40° C. After the addition wascompleted, the reaction mixture was heated at 40° C. for an additionalhour. The cooled reaction mixture was poured over ice and made basic topH 9 with concentrated ammonium hydroxide. The reaction mixture wasextracted with ethyl acetate (4×). The combined organic extracts weredried over sodium sulfate, filtered, and concentrated in vacuo.Purification by column chromatography (120 g silica; 90:10 hexane/ethylacetate) provided7-bromo-2-methyl-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline (1.05 g, 40%).This product was resolved by chrial HPLC (Chiralpak AD, 95:5heptane/isopropanol with 0.1% diethylamine). The (+)enantiomer (430 mg,41%) was obtained as a clear oil: [α]²⁵ _(d)+11.9° (0.2, methanol); ¹HNMR (500 MHz, CDCl₃) δ 7.22 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.09 (d,J=7.9 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 6.74 (d, J=8.5 Hz, 1H), 4.03-3.98(m, 1H), 3.70 (d, J=15.0 Hz, 1H), 3.56 (d, J=15.0 Hz, 1H), 3.01-2.98 (m,1H), 2.53-2.49 (m, 1H), 2.40 (s, 3H), 2.32 (s, 3H).

Step D: A mixture of the product ((+)-enantiomer) from Step C (430 mg,1.36 mmol), bis(pinacole)diborane (380 mg, 1.50 mmol), and KOAc (400 mg,4.08 mmol) was degassed with argon. To this mixture was addedPdCl₂(dppf) (67 mg, 0.082 mmol). The resulting mixture was degassed withargon and then heated to reflux for 6 hours. After completion bythin-layer chromatography analysis the cooled material was diluted withwater and the organic layer was separated. The aqueous layer wasextracted with ethyl acetate (3×). The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered, and concentratedin vacuo to afford2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-p-tolyl-1,2,3,4-tetrahydroisoquinolineas a brown oil, which was used in Step E without further purification:¹H NMR (500 MHz, CDCl₃) δ 7.54 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.10 (d,J=7.9 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.88 (d, J=7.7 Hz, 1H), 4.38 (brs, 1H), 3.94-3.91 (m, 1H), 3.75-3.72 (m, 1H), 3.16-3.14 (m, 1H), 2.61(s, 3H), 2.52 (s, 1H), 2.32 (s, 3H), 1.33 (s, 6H), 1.25 (s, 6H).

Step E: A mixture of the crude product from Step D (490 mg, 1.35 mmol),3-chloro-6-methyl-pyridazine (217 mg, 1.69 mmol), and cesium carbonate(1.32 g, 4.05 mmol) in DMF (15 mL) and water (3 mL) was degassed withargon. To this mixture was added PdCl₂(dppf) (66 mg, 0.08 mmol). Theresulting mixture was degassed with argon and then heated to reflux for5 hours. After completion by thin-layer chromatography analysis thecooled material was filtered through a bed of diatomaceous earth andwashed with water (3×). The organic layers were separated, dried oversodium sulfate, filtered, and concentrated in vacuo. After purificationby semi-preparative HPLC (95:5 acetonitrile/water gradient over 40minutes), the material was free-based with sodium bicarbonate to afford2-methyl-7-(6-methylpyridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline(95 mg, 21%) as a light-yellow solid; ¹H NMR (500 MHz, CDCl₃) δ 7.86 (s,1H), 7.71-7.68, (m, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.13-7.09 (m, 4H), 7.01(d, J=8.1 Hz, 1H), 4.30 (t, J=7.6 Hz, 1H), 3.87 (d, J=15.0 Hz, 1H), 3.70(d, J=14.9 Hz, 1H), 3.08-3.05 (m, 1H), 2.74 (s, 3H), 2.59 (t, J=9.4 Hz,1H), 2.46 (s, 3H), 2.33 (s, 3H).

Step F: To a solution of the product from Step E above (270 mg, 0.820mmol) in 1,2-dichloroethane (20 mL) at 0° C. was added proton sponge(184 mg, 0.860 mmol) and 1-chloroethyl chloroformate (234 mg, 1.64 mmol)dropwise. The resultant mixture was heated at reflux for 20 hours, andthe mixture was concentrated in vacuo. The crude product obtained waspurified by flash column chromatography (100% methylene chloride to 100%methylene chloride:methanol:concentrated ammonium hydroxide 90:8:2) togive the desired intermediate which was taken up in methanol (5.0 mL),refluxed for 2 hours. The reaction mixture was partitioned withsaturated sodium bicarbonate (50 mL) and methylene chloride (2×50 mL),dried over sodium sulfate, and concentrated in vacuo. The crude productobtained was purified by flash column chromatography (100% methylenechloride to 100% methylene chloride:methanol:concentrated ammoniumhydroxide 80:18:2) to give7-(6-Methylpridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroquinoline (60 mg,23%) as an orange liquid. To a solution of the newly obtainedtetrahydroisoquinoline (35 mg, 0.11 mmol) in methanol (2 mL) was addedL-tartaric acid (16.8 mg, 0.11 mmol) followed by slow addition of water(10 mL). The resultant solution was lyophilized overnight to give7-(6-methylpridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroquinoline,L-tartrate salt (98.1% AUC HPLC) as a light brown solid: ¹H NMR (D₂O,300 MHz) δ 8.14 (d, J=9.5 Hz, 1H), 7.86 (d, J=9.5 Hz, 2H), 7.88 (dd,J=8.5, 1.5 Hz, 1H), 7.28 (d, J=9.5 Hz, 2H), 7.14-7.20 (m, 3H), 4.56-4.77(m, 4H), 4.54 (s, 2H), 3.86 (dd, J=6.5, 4.5 Hz, 1H), 3.54 (dd, J=8.5,1.5 Hz, 1H), 2.74 (s, 3H), 2.34 (s, 3H); ESI MS m/z 316 [M+H]⁺; [α]²³_(D) +6.9° (c 0.09, methanol).

Example 2 Preparation of(+)-6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine,L-tartrate Salt

Step A: To a mixture of(+)-7-bromo-4-(4-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline(184 mg, 0.58 mmol, prepared following similar methods described in StepA to Step C of Example 1 starting from2-bromo-1-(4-fluorophenyl)ethanone and1-(3-bromophenyl)-N-methylmethanamine), and proton sponge (123 mg, 0.58mmol) in 1,2-dichloroethane (3 mL) was added 1-chloroethyl chloroformate(0.50 mL, 4.60 mmol) at 0° C. under a nitrogen atmosphere. The reactionmixture was stirred at 0° C. for 1 hour and then allowed to warm toambient temperature overnight. The mixture was quenched with 1N HCl indiethyl ether (10 mL), concentrated under reduced pressure to give theintermediate 2-chloroethylcarbamate. The intermediate was dissolved inmethanol and heated at 70° C. for 3 hours before concentrating underreduced pressure to 4 mL volume. The solution was treated withdi-tert-butyl-dicarbonate (252 mg, 1.16 mmol) and 2N NaOH (3 mL) withstirring overnight then partitioned between ethyl acetate (20 mL) andbrine. The organic layer was dried over sodium sulfate and concentratedunder reduced pressure to give the crude material which was purified byflash column chromatography (90:5 to 80:20 hexanes/ethyl acetate) togive tert-butyl7-bromo-4-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(112 mg, 48%) as a white semi-solid: ¹H NMR (CDCl₃, 300 MHz) δ 7.33 (s,1H), 7.25 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.98-6.93 (m, 4H), 6.81 (d, J=8.4Hz, 1H), 4.95-4.44 (m, 2H), 4.09-4.07 (m, 1H), 3.90-3.82 (m, 1H), 3.87(br s, 1H), 3.64 (br d, J=8.7 Hz, 1H), 1.44 (br s, 3H), 1.25 (br s, 6H);ESI MS m/z 306 [M-O₅H₉O₂+H]⁺.

Step B: To a solution of tert-butyl7-bromo-4-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(110 mg, 0.27 mmol) in DMSO (2 mL) was added bis(pinacolato)diboron (76mg, 0.30 mmol), potassium acetate (80 mg, 0.81 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.01mmol). The reaction flask was purged with nitrogen and heated at 85° C.for 4 hours. The reaction mixture was cooled to ambient temperature anddi-tert-butyl 6-chloropyridazin-3-yliminodicarbonate (116 mg, 0.35mmol), cesium carbonate (265 mg, 0.81 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.01mmol), and water (0.3 mL) was added. The reaction flask was purged withnitrogen and heated at 85° C. for 2 hours. The reaction mixture wascooled to ambient temperature then partitioned between ethyl acetate (50mL) and water (30 mL). The organic layer was washed with water and brinethen dried over sodium sulfate. Concentration in vacuo and purificationby flash column chromatography (80:20 to 50:50 hexanes/ethyl acetate)afforded tert-butyl7-(6-(bis(tert-butoxycarbonyl)amino)pyridazin-3-yl)-4-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatewhich was deprotected directly by treating with trifluoroacetic acid (2mL) in dichloromethane (2 mL) for 1 hour. The residue was concentratedin vacuo, partitioned between dichloromethane and saturated sodiumbicarbonate solution. The organic layer was washed with brine then driedover sodium sulfate. Concentration in vacuo gave the crude materialwhich was purified by flash column chromatography (90:9:1dichloromethane/methanol/ammonium hydroxide) to give6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine(38 mg, 44%): ESI MS m/z 321 [M+H]⁺.

Step C: To a solution of(+)-6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine(38 mg, 0.12 mmol) in methanol (3.6 mL) was added L-tartaric acid (18mg, 0.12 mmol). The mixture was sonicated for 2 minutes, diluted withwater (20 mL), and lyophilized to give the correspondent tartrate salt(61 mg, 86%, AUC HPLC 97.9%) as a white solid. ¹H NMR (CD₃OD, 300 MHz) δ7.85 (s, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.75 (dd, J=8.3 Hz, 1.5 Hz, 1H),7.30 (dd, J=8.7 Hz, 5.4 Hz, 2H), 7.13 (t, J=8.7 Hz, 2H), 7.04 (d, J=9.3Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 4.65-4.49 (m, 3H), 4.42 (s, 2H), 3.78(dd, J=12.8 Hz, 6.0 Hz, 1H), 3.45 (dd, J=12.5 Hz, 11.1 Hz, 1H); ESI MSm/z 321 [M+H]⁺. Anal. calcd. C₁₉H₁₇FN₄.1.5C₄H₆O₆.2.7H₂O: C, 50.54; H,5.33; N, 9.43. Found C, 50.50; H, 4.96; N, 9.23.

Example 3 Preparation of(+)-6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine,L-tartarate Salt

Step A:(+)-4-(4-Fluorophenyl)-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolinewas prepared following similar methods described in Step A to Step D ofExample 1 starting from 2-bromo-1-(4-fluorophenyl)ethanone.

To a mixture of4-(4-fluorophenyl)-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(1.13 g, 3.08 mmol), and tert-butyl6-chloropyridazin-3-yl(methyl)carbamate (751 mg, 3.08 mmol) in DMF (15mL) and water (3 mL) was added cesium carbonate (4.01 g, 12.3 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.06mmol). The reaction flask was evacuated and back filled with nitrogen.After heating the reaction mixture at 85° C. for 4 hours, it was cooledto ambient temperature then partitioned between ethyl acetate (300 mL)and water (150 mL). The organic layer was washed with water and brinethen dried over sodium sulfate. Concentration in vacuo gave the crudematerial which was purified by flash column chromatography to givetert-butyl6-(4-(4-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-yl(methyl)carbamate(1.24 g, 90%) as an orange/brown foam: ¹H NMR (CDCl₃, 500 MHz) δ 8.12(d, J=9.5 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.75-7.70 (m, 2H), 7.19 (dd,J=8.8 Hz, 5.0 Hz, 2H), 7.01-6.97 (m, 3H), 4.30 ((brs, 1H), 3.82 (d,J=14.5 Hz, 1H), 3.71 (d, J=14.5 Hz, 1H), 3.61 (s, 3H), 3.08-3.05 (m,1H), 2.59 (dd, J=11.5 Hz, 8.0 Hz, 1H), 2.46 (s, 3H), 1.56 (s, 9H); ESIMS m/z 449 [M+H]⁺.

Step B: To a mixture of the product from Step A (428 mg, 0.96 mmol) andproton sponge (102 mg, 0.50 mmol) in 1,2-dichloroethane (3 mL) was added1-chloroethyl chloroformate (208 μL, 1.91 mmol) at 0° C. under anitrogen atmosphere. The reaction mixture was allowed to warm to ambienttemperature over a weekend and concentrated in vacuo. The intermediate2-chloroethylcarbamate was purified by flash column chromatography(dichloromethane) and refluxed in methanol for 3 hours. The resultingsolution was concentrated under reduced pressure and treated withtrifluoroacetic acid (5 mL) in dichloromethane (5 mL) for 1 hour. Afterconcentration in vacuo, the residue was partitioned betweendichloromethane (30 mL) and 2N aqueous sodium hydroxide (10 mL). Theorganic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo to give the crude material which was purified byflash column chromatography (90:10 to 50:50 ethyl acetate/ethylacetate:methanol:ammonium hydroxide) to give6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine(65 mg, 20%) as a colorless oil: [α]^(D)=+18.0° (0.05, methanol): ¹H NMR(CDCl₃, 300 MHz) δ 7.76 (d, J=1.2 Hz, 1H), 7.66 (dd, J=8.1 Hz, 1.8 Hz,1H), 7.58 (d, J=9.6 Hz, 1H), 7.12-7.06 (m, 2H), 7.03-6.95 (m, 2H), 6.99(t, J=8.4 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 4.95 (d, J=5.1 Hz, 1H),4.26-4.09 (m, 2H), 3.42 (dd, J=12.9 Hz, 5.1 Hz, 1H), 3.11-3.05 (m, 4H),1.96 (br s, 2H); ESI MS m/z 335 [M+H]⁺.

Step C: To a solution of6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine(64 mg, 0.19 mmol) in methanol (2 mL) and water (2 mL) was addedL-tartaric acid (29 mg, 0.19 mmol). The mixture was sonicated, dilutedwith water (12 mL) and lyophilized to give the correspondent L-tartaratesalt ((+)-enantiomer) (97 mg, 87%, AUC HPLC 97.9%) as a white solid. ¹HNMR (CD₃OD, 300 MHz) δ 7.87 (s, 1H), 7.76 (d, J=9.6 Hz, 2H), 7.33-7.28(m, 1H), 7.30 (dd, J=8.7 Hz, 5.4 Hz, 1H), 7.13 (t, J=8.7 Hz, 2H), 6.99(d, J=8.1 Hz, 1H), 6.97 (d, J=9.3 Hz, 1H), 4.65-4.54 (m, 3H), 4.42 (s,2H), 3.78 (dd, J=12.6 Hz, 5.7 Hz, 1H), 3.45 (t, J=11.1 Hz, 1H), 3.01 (s,3H); ESI MS m/z 335 [M+H]⁺. Anal. calcd. C₂₀H₁₉FN₄.1.4C₄H₆O₆.2H₂O: C,52.96; H, 5.45; N, 9.65. Found C, 53.13; H, 5.47; N, 9.70.

Example 4 Preparation of(+)-4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroquinoline,L-tartrate Salt

Step A:(+)-4-(4-Chlorophenyl)-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinolinewas prepared following similar methods described in Step A to Step E ofExample 1 starting from 2-bromo-1-(4-chlorophenyl)ethanone and1-(3-bromophenyl)-N-methylmethanamine.

To a solution of4-(4-chlorophenyl)-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(69 mg, 0.17 mmol) in 1,2-dichloroethane (5 mL) at 0° C. was addedproton sponge (37 mg, 0.17 mmol) and 1-chloroethyl chloroformate (56 μL,0.51 mmol) dropwise. The resultant mixture was stirred at 0° C. for onehour and then heated at reflux for 1.5 hours. After concentrating themixture in vacuo, the crude intermediate was taken up in methanol (5.0mL) and heated at reflux for 1 hour. After concentrating in vacuo, thecrude product obtained was purified by preparative thin layerchromatography using 90:9:1 ethyl acetate/methanol/concentrated ammoniumhydroxide as eluent to give4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(22 mg, 33%) as a light yellow oil: [α]²³ _(D) +7.5° (c 0.08, methanol).To a solution of the newly obtained tetrahydroisoquinoline (20 mg, 0.051mmol) in acetonitrile (1 mL) was added L-tartaric acid (8 mg, 0.051mmol) followed by slow addition of water (4 mL). The resultant solutionwas lyophilized for two days to give the correspondent L-tartrate salt(>99% AUC HPLC) as an off-white solid: ¹H NMR (CD₃OD, 500 MHz) δ 8.39(d, J=9.0 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.17 (s, 1H), 8.03 (dd,J=8.0, 2.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.11(d, J=8.5 Hz, 1H), 4.65-4.53 (m, 3H), 4.42 (s, 2H), 3.80-3.76 (m, 1H),3.47-3.43 (m, 1H); ESI MS m/z 390 [M+H]⁺.

Example 5 Preparation of(+)-6-(4-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine,L-tartrate Salt

Step A: To an ice-cold solution of the(+)-7-bromo-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline(400 mg, 1.2 mmol) which was prepared following similar methodsdescribed in Step A to Step C of Example 1 starting from2-bromo-1-(4-chlorophenyl)ethanone and1-(3-bromophenyl)-N-methylmethanamine, and proton sponge(N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine, 77 mg, 0.4 mmol) in1,2-dichloroethane (6 mL) was added 1-chloroethyl chloroformate (0.16mL, 1.4 mmol) drop wise. The mixture was stirred for 15 minutes and thenheated to reflux for 3 hours. Additional 1-chloroethyl chloroformate(0.16 mL, 1.4 mmol) and proton sponge (77 mg, 0.4 mmol) were added. Themixture heated to reflux for 2 days, then cooled to room temperature andconcentrated. The residue was dissolved in methanol (10 mL) and heatedto reflux for 1.5 hours. The mixture was cooled to room temperature,concentrated and the residue dissolved in dichloromethane (10 mL).Di-tert-butyl dicarbonate (314 mg, 1.4 mmol) was added and the mixturestirred overnight. The mixture was partitioned between ethyl acetate andbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated. Purification by column chromatography (hexanes to 1:1hexanes/ethyl acetate) gave tert-butyl7-bromo-4-(4-chlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(360 mg, 71%) as a tan solid (mixture of rotamers): ¹H NMR (CDCl₃, 500MHz) δ 7.34 (br s, 1H), 7.30-7.22 (m, 3H), 7.05-6.93 (m, 2H), 6.82-6.78(m, 1H), 5.00-4.38 (m, 2H), 4.08 (br s, 1H), 3.98-3.50 (m, 2H),1.49-1.16 (m, 9H); ESI MS m/z 322 [M+H-Boc]⁺.

Step B: A mixture of the protected bromotetrahydroisoquinoline (360 mg,0.85 mmol), bis(pinacolato)diboron (239 mg, 0.94 mmol) and potassiumacetate (255 mg, 2.6 mmol) in DMSO (5 mL) was degassed with argon, andthen dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (29 mg,0.04 mmol) was added. The mixture was degassed again and then heated to50° C. for 2 hours. The mixture was partitioned with water and ethylacetate (3×) and the combined organic extracts were washed with brine,dried over sodium sulfate, filtered, and concentrated to a brown oilused directly in the next reaction without purification.

A solution of the boronate ester (400 mg, 0.85 mmol) from above, cesiumcarbonate (1.2 g, 3.4 mmol) and bis-Boc protected6-chloro-N,N-pyridazine-3-amine (421 mg, 1.3 mmol) in DMF (5 mL) andwater (1 mL) was degassed with argon, bis(diphenylphosphino)ferrocenepalladium(II) (29 mg, 0.04 mmol) was added, the mixture degassed again,and then stirred at room temperature overnight. The mixture waspartitioned with water and ethyl acetate (3×). The combined organicextracts were washed with brine, dried over sodium sulfate, filtered,and concentrated. The residue was purified by column chromatography(hexanes to 1:1 hexanes/ethyl acetate) to give the coupledtetrahydroisoquinoline (225 mg, 41%) product as an off-white solid. To asolution of this tetrahydroisoquinoline (240 mg, 0.38 mmol) indichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and thenthe mixture stirred at room temperature for 3 hours. The mixture wasconcentrated and the residue partitioned with saturated sodiumbicarbonate and ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, and concentrated. The residue was purified bysemi-preparative HPLC to give the de-protected tetrahydroisoquinoline(82 mg, 64%) as a yellow oil.

A suspension of the above tetrahydroisoquinoline (44 mg, 0.13 mmol) andL-tartaric acid (18 mg, 0.13 mmol) in MeOH was sonicated for 5 minutesand then concentrated. The residue was dissolved in acetonitrile andwater, and then lyophilized overnight to give(+)-6-(4-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine,L-tartrate salt (34 mg, 23%, AUC HPLC>99%) as a white solid: ¹H NMR(DMSO-d₆, 500 MHz) δ 7.85 (d, J=1.5 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H),7.73 (dd, J=8.5, 2.0 Hz, 1H), 7.43-7.41 (m, 2H), 7.30-7.28 (m, 2H),6.85-6.83 (m, 2H), 6.49 (s, 2H), 4.38-4.35 (m, 2H), 4.29-4.26 (m, 1H),4.07 (s, 1.4H), 3.53 (dd, J=12.5, 5.5 Hz, 1H), 3.22 (dd, J=12.0, 9.5 Hz,1H); ESI MS m/z 337 [M+H]⁺.

Example 6 Preparation of4-(4-Chloro-phenyl)-7-(6-chloro-pyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline

Step A: To a mixture of 3-bromoacetophenone (8.21 g, 40 mmol) andammonium acetate (30.8 g, 0.4 mol) in methanol (100 mL) was added sodiumcyanoborohydride (1.76 g, 28 mmol). The reaction mixture was stirred atroom temperature for 3 days and then concentrated HCl was added untilpH<2. The resulting ammonium chloride precipitate was filtered off andwashed with water. The filtrate was concentrated under reduced pressure.To the residue was added water (100 mL). The resulting precipitate wascollected by filtration and washed with water, dried at 60° C. undervacuum to afford 3.1 g of white solid which contained a mixture ofbenzyl amine (desired product) and dibenzyl amine in 1:1.2 ratio. Thefiltrate was adjusted to pH>10 with solid KOH and extracted withdichloromethane (3×100 mL). The combined extracts were dried over sodiumsulfate and concentrated to provide 1-(3-bromophenyl)ethanamine (4.65 g,58%) as a white solid: ¹H NMR (CDCl₃, 300 MHz) δ 7.51 (t, J=1.7 Hz, 1H),7.38-7.34 (m, 1H), 7.28-7.25 (m, 1H), 7.19 (t, J=7.7 Hz, 1H), 4.09 (q,J=6.6 Hz, 1H), 1.37 (d, J=6.6 Hz, 3H). ESI MS m/z=200 [M+H]⁺.

Step B: To an ice-cooled mixture of the product from Step A (4.6 g, 23mmol) and diisopropylethylamine (4.46 g, 34.5 mmol) in dichloromethane(50 mL) was added 2-bromo-4′-chloroacetophenone (5.48 g, 23 mmol). Thereaction mixture was stirred at room temperature for 3 hours and thendiluted with dichloromethane (100 mL). The mixture was washed with waterand brine, dried over sodium sulfate, and concentrated. Flashchromatography (silica gel, 20 to 40% ethyl acetate/hexanes)purification provided the2-(1-(3-bromophenyl)ethylamino)-1-(4-chlorophenyl)ethanone (6.0 g, 74%):¹H NMR (CDCl₃, 300 MHz) δ 7.80 (dd, J=6.7, 2.0 Hz, 2H), 7.52 (t, J=1.7Hz, 1H), 7.43-7.37 (m, 3H), 7.29-7.17 (m, 2H), 3.93 (d, J=1.4 Hz, 2H),3.80 (q, J=6.6 Hz, 1H), 1.42 (d, J=6.6 Hz, 3H). ESI MS m/z=352 [M+H]⁺.

Step C: To an ice-cooled solution of the product from Step B (5.97 g,16.9 mmol) in methanol (90 mL) was added sodium borohydride (703 mg,18.6 mmol). The reaction mixture was stirred at 0° C. for 1 hour. Thesolvent was removed under reduced pressure. The residue was partitionedbetween dichloromethane and water. The aqueous was extracted withdichloromethane (2×). The combined extracts were washed with brine,dried over sodium sulfate, and concentrated to provide the desiredalcohol (5.98 g, 99% crude yield): ESI MS m/z=354 [M+H]⁺. This crudeproduct was used in the next step without further purification.

Step D: To an ice-cooled solution of the crude product from Step C (5.98g, 16.9 mmol) in dichloromethane (70 mL) was added concentrated sulfuricacid (4.2 mL) dropwise. The reaction mixture was stirred at 0° C. for 2hours and the adjusted to pH>8 by adding saturated sodium bicarbonate.The organic layer was separated and the aqueous was extracted withdichloromethane (2×). The combined extracts were washed with brine,dried over sodium sulfate, and concentrated. Purification by columnchromatography (silica gel, 0 to 4% methanol/dichloromethane) provided7-bromo-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline as asingle diastereomer (1.19 g, 21%): ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (d,J=1.8 Hz, 1H), 7.28-7.24 (m, 2H), 7.19 (dd, J=8.3, 2.0 Hz, 1H),7.03-6.98 (m, 2H), 6.69 (d, J=8.3 Hz, 1H), 4.19 (q, J=6.6 Hz, 1H), 4.03(dd, J=8.1, 5.7 Hz, 1H), 3.42 (dd, J=12.9, 5.5 Hz, 1H), 2.94 (dd,J=12.9, 8.4 Hz, 1H), 1.49 (d, J=6.7 Hz, 3H). ESI MS m/z=336 [M+H]⁺.

Step E: Bis(pinacolato)diboron (531 mg, 2.09 mmol) was added to amixture of the product from Step D (640 mg, 1.90 mmol) and potassiumacetate (559 mg, 5.70 mmol) in dimethyl sulfoxide (10 mL). The reactionmixture was degassed with argon. PdCl₂(dppf)(CH₂Cl₂) (78 mg, 0.095 mmol)was added and the reaction mixture was stirred at 80° C. for 1 hour,cooled, diluted with water, and extracted with ethyl acetate (2×). Thecombined organic extracts were washed with brine, dried over anhydroussodium sulfate, and concentrated to give the desired boronate (880mg, >99% crude yield). ESI MS m/z=384 [M+H]⁺. This crude product wasused in the next step without further purification.

Step F: 3,6-Dichloropyridazine (350 mg, 2.28 mmol) was added to amixture of the crude product from Step E (880 mg, 1.90 mmol) and sodiumcarbonate (604 mg, 5.70 mmol) in dimethylformamide (10 mL) and water(2.5 mL). The reaction mixture was degassed with argon.PdCl₂(dppf)(CH₂Cl₂) (93 mg, 0.114 mmol) was added and the reactionmixture was stirred at 80° C. for 2 hours, cooled, diluted with water,and extracted with ethyl acetate (2×). The combined organic extractswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated. Purification by column chromatography (silica gel, 0% to5% MeOH/CH₂Cl₂ gave4-(4-chloro-phenyl)-7-(6-chloro-pyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline(490 mg, 70% for 3 steps): ¹H NMR (CDCl₃, 500 MHz) δ 8.00 (d, J=1.1 Hz,1H), 7.80 (d, J=9.0 Hz, 1H), 7.66 (dd, J=8.1, 1.8 Hz, 1H), 7.55 (d,J=8.9 Hz, 1H), 7.30-7.26 (m, 2H), 7.08-7.05 (m, 2H), 6.98 (d, J=8.1 Hz,1H), 4.33 (q, J=6.6 Hz, 1H), 4.20-4.17 (m, 1H), 3.49 (dd, J=12.8, 5.5Hz, 1H), 3.02 (dd, J=12.8, 8.4 Hz, 1H), 1.58 (d, J=6.7 Hz, 3H). ESI MSm/z=370 [M+H]⁺.

Example 7 Preparation of4-(4-Chloro-phenyl)-7-(pyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline

Step A: To a solution of the product from Step F of Example 6, (190 mg,0.51 mmol) in ethanol (15 mL) was added hydrazine (1 mL, 20.6 mmol) and10% Pd/C (100 mg). The reaction mixture was heated at reflux for 1 hour.The mixture was then filtered through celite and the celite bed waswashed with methanol. The filtrate was concentrated and purified bycolumn chromatography (silica gel, 1% to 5% MeOH/CH₂Cl₂) to provide4-(4-Chloro-phenyl)-7-(pyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline(99 mg, 57%): ¹H NMR (CDCl₃, 500 MHz) δ 9.15 (dd, J=4.9, 1.6 Hz, 1H),8.05 (d, J=1.3 Hz, 1H), 7.83 (dd, J=8.6, 1.6 Hz, 1H), 7.69 (dd, J=8.1,1.8 Hz, 1H), 7.53 (dd, J=8.6, 4.9 Hz, 1H), 7.29-7.26 (m, 2H), 7.08-7.05(m, 2H), 6.98 (d, J=8.1 Hz, 1H), 4.35-4.33 (m, 1H), 4.19 (dd, J=7.9, 5.8Hz, 1H), 3.49 (dd, J=12.8, 5.5 Hz, 1H), 3.02 (dd, J=12.8, 8.3 Hz, 1H),1.59 (d, J=6.7 Hz, 3H). ESI MS m/z=336 [M+H]⁺.

Example 8 Preparation of4-(4-Chloro-phenyl)-7-(6-methoxy-pyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline

Step A: To a solution of the product from Step B of Example 6 (240 mg,0.648 mmol) in methanol (5 mL) was added sodium methoxide (25 wt % inmethanol, 2 mL). The reaction mixture was heated at reflux for 1 hour.The solvent was removed under reduced pressure and the residue wasdiluted with ethyl acetate (50 mL). The solution was washed with brine,dried over anhydrous sodium sulfate, and concentrated. Purification bycolumn chromatography (silica gel, 0% to 5% MeOH/CH₂Cl₂) gave the4-(4-chloro-phenyl)-7-(6-methoxy-pyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline(171 mg, 72%): ¹H NMR (CDCl₃, 500 MHz) δ 7.99 (s, 1H), 7.76 (d, J=9.2Hz, 1H), 7.62 (dd, J=8.1, 1.7 Hz, 1H), 7.29-7.26 (m, 2H), 7.08-7.03 (m,3H), 6.94 (d, J=8.1 Hz, 1H), 4.32 (q, J=6.7 Hz, 1H), 4.19 (s, 3H),4.19-4.15 (m, 1H), 3.49 (dd, J=12.8, 5.5 Hz, 1H), 3.02 (dd, J=12.8, 8.4Hz, 1H), 1.58 (d, J=6.7 Hz, 3H). ESI MS m/z=366 [M+H]⁺.

Example 9 Preparation of (+)- and(−)-4-(3,4-dichlorophenyl)-7-(pyrazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydro-isoquinoline

Step A: Cerium(III) chloride heptahydrate (29.8 g, 80 mmol) was driedwith magnetic stirring at 145° C. under vacuum overnight.Tetrahydrofuran (160 mL) was added and the white suspension was stirredat room temperature for 2 hours and then cooled with dry-ice/acetonebath. To this dry-ice/acetone bath cooled solution was added methyllithium (1.6 M in ether, 50 mL, 80 mmol). The reaction mixture wasstirred for 30 minutes and then a solution of 3-bromobenzonitrile (3.68g, 20 mmol) in tetrahydrofuran (10 mL) was added. The resulting reactionmixture was stirred at −70 to −60° C. for 5 hours. Concentrated ammoniumhydroxide (50 mL) was added at −40° C. The mixture was allowed to warmto room temperature and filtered through Celite. The Celite bed waswashed with dichloromethane. The filtrate was extracted withdichloromethane (3×). The combined extracts were washed with brine,dried over sodium sulfate, and concentrated under reduced pressure togive 1,1-dimethyl-3′-bromobenzyl amine (4.33 g, >99% crude) as a clearoil, which was used in the next step without further purification: ESIMS m/z 214 [M+H]⁺.

Step B: To an ice-cooled solution of 1,1-dimethyl-3′-bromobenzyl amine(3.82 g, 17.8 mmol) from Step A above in dichloromethane (100 mL) wasadded diisopropylethylamine (3.45 g, 26.7 mmol) and2-bromo-3′,4′-dichloroacetophenone (2.44 g, 8.92 mmol). The reactionmixture was stirred at room temperature for 2 days. The mixture wasdiluted with dichloromethane (50 mL), and washed with water and brine,dried over sodium sulfate, and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography (10 to 30%ethyl acetate/hexanes) to give2-(2-(3-bromophenyl)propan-2-ylamino)-1-(3,4-dichlorophenyl)ethanone(1.37 g, 38% over 2 steps): ¹H NMR (CDCl₃, 500 MHz) δ 7.92 (d, J=2.0 Hz,2H), 7.67 (dd, J=8.4, 2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.51 (d,J=8.4 Hz, 1H), 7.37-7.35 (m, 2H), 7.20 (t, J=7.9 Hz, 1H), 3.83 (s, 2H),1.51 (s, 6H).

Step C: To a solution of the ketone (1.37 g, 3.41 mmol) from Step Babove in methanol (40 mL) at 0° C. was added sodium borohydride (133 mg,3.5 mmol). The reaction mixture was stirred at 0° C. for 1 hour. Thesolvent was then removed under reduced pressure and the residue wasdissolved in dichloromethane. The resultant solution was washed withbrine, dried over sodium sulfate, and concentrated under reducedpressure to give the desired alcohol (1.35 g, 98% crude). The crudeproduct was used in the next step without further purification: ESI MSm/z 404 [M+H]⁺.

Step D: To an ice-cooled solution of the alcohol (1.35 g, 3.35 mmol)from Step C above in dichloromethane (80 mL) was added concentratedsulfuric acid (8 mL) dropwise. The reaction solution was stirred at roomtemperature for 16 hours, and then was added slowly to ice-coldsaturated sodium bicarbonate. The organic layer was separated and theaqueous layer was extracted with dichloromethane (2×). The combinedorganic extracts were washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. The crude product was purified byflash column chromatography (20 to 50% ethyl acetate/hexanes) to give7-bromo-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline(113 mg, 9%): ¹H NMR (CDCl₃, 500 MHz) δ 7.42 (d, J=2.0 Hz, 1H), 7.36 (d,J=8.2 Hz, 1H), 7.21 (dd, J=8.3, 2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H),6.88 (dd, J=8.3, 2.0 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 3.95 (t, J=5.2 Hz,1H), 3.38 (dd, J=13.5, 5.0 Hz, 1H), 3.03 (dd, J=13.5, 5.6 Hz, 1H), 1.52(s, 3H), 1.47 (s, 3H); ESI MS m/z 386 [M+H]⁺.

Step E: To a mixture of the product (113 mg, 0.293 mmol) from Step Dabove, bis(pinacolato)diboron (82 mg, 0.323 mmol), and potassium acetate(87 g, 0.88 mmol) was added dimethyl sulfoxide (4 mL). The resultantsolution was purged with argon for 10 minutes, and thendichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (24 mg, 0.029 mmol) was added to it. The reactionsolution was degassed again with argon for 5 minutes and heated at 80°C. for 1 hour. The reaction solution was then cooled to roomtemperature, diluted with ethyl acetate, washed with brine, dried oversodium sulfate, and concentrated under reduced pressure to give thedesired boronate ester (190 mg, crude) which was used in the next stepwithout further purification: ESI MS m/z 432 [M+H]⁺.

Step F: 3-Chloropyridazine (51 mg, 0.44 mmol) was added to a mixture ofthe boronate ester from Step E (0.293 mmol, crude) and cesium carbonate(287 mg, 0.88 mmol) in DMF (3 mL) and water (0.4 mL). The reactionmixture was degassed with argon.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (24 mg, 0.029 mmol) was added and the reactionmixture was stirred at 90° C. for 2 hours, cooled, diluted with waterand extracted with ethyl acetate (3×). The combined organic extractswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated. Purification by flash column chromatography (2 to 5%methanol/dichloromethane) followed by preparative HPLC gave4-(3,4-dichlorophenyl)-1,1-dimethyl-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(37 mg, 33% over 2 steps): ¹H NMR (CDCl₃, 500 MHz) δ 9.16 (dd, J=4.9,1.5 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 7.85 (dd, J=8.6, 1.5 Hz, 1H), 7.70(dd, J=8.0, 1.8 Hz, 1H), 7.54 (dd, J=8.6, 4.9 Hz, 1H), 7.38 (d, J=8.2Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.95 (dd,J=8.2, 2.0 Hz, 1H), 4.10 (t, J=5.2 Hz, 1H), 3.46 (dd, J=13.4, 5.0 Hz,1H), 3.10 (dd, J=13.4, 5.6 Hz, 1H), 1.63 (s, 3H), 1.58 (s, 3H); ESI MSm/z 384 [M+H]⁺.

Step G: The product from Step F (28 mg) was resolved by preparativechiral HPLC (ChiralCel OD column, using 85:15:0.1heptane/ethanol/diethylamine as the eluent) to give the (+)-enantiomer([α]²⁵ _(D) +33.0° (c 0.20, methanol)) and the (−)-enantiomer ([α]²⁵_(D) −38.0° (c 0.20, methanol)).

Example 10 Preparation of (+)- and(−)-4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

Step A: To a solution of 2-bromo-1-(3,4-dichlorophenyl)ethanone (5.1 g,18.96 mmol) in methanol (50 mL) at 0° C. was added sodium borohydride(2.1 g, 56.98 mmol). The reaction mixture was stirred at 0° C. for 1hour. The pH was adjusted to 12 using 2 M sodium hydroxide solution, thesolvent was then removed under reduced pressure and the residue wasdissolved in dichloromethane. The resultant solution was washed withbrine, dried over sodium sulfate, and concentrated under reducedpressure to give 2-(3,4-dichlorophenyl)oxirane (1.79 g, 50% crude). Thecrude product was used in the next step without further purification: ¹HNMR (CDCl₃, 500 MHz) δ 7.41 (d, J=8.5 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H),7.12 (dd, J=8.5, 2.0 Hz, 1H), 3.81 (dd, J=4.0, 2.5 Hz, 1H), 3.14 (dd,J=5.5, 4.0 Hz, 1H), 2.73 (dd, J=5.5, 2.5 Hz, 1H); ESI MS m/z 189 [M]⁺.

Step B: A solution of 1,1-dimethyl-3′-bromobenzyl amine (1.18 g, 5.51mmol) which was prepared in Step A of Example 9, and the epoxide fromStep A (0.95 g, 5.02 mmol) in ethanol (10 mL) was heated at 90° C. for17 hours. The mixture was concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography (0 to 100% ethylacetate in hexanes) to afford2-(2-(3-bromophenyl)propan-2-ylamino)-1-(3,4-dichlorophenyl)ethanol(1.46 g, 72%): ¹H NMR (CDCl₃, 500 MHz) δ 7.51 (d, J=2.0 Hz, 1H),7.45-7.34 (m, 4H), 7.20 (t, J=8.0 Hz, 1H), 7.12 (dd, J=2.0, 8.5 Hz, 1H),4.54 (dd, J=3.5, 8.5 Hz, 1H), 3.49 (s, 1H), 2.65 (dd, J=12.5, 3.5 Hz,1H); 2.35 (dd, J=12.5, 8.5 Hz, 1H), 1.58 (s, 1H), 1.47 (s, 3H), 1.46 (s,3H); ESI MS m/z 404 [M+H]⁺.

Step C: To an ice-cooled solution of the alcohol (920 mg, 2.49 mmol)from Step B above in dichloromethane (60 mL) was added concentratedsulfuric acid (6 mL) drop-wise. The reaction solution was stirred at 0°C. for 5 hours, and then was added slowly to ice-cold saturated sodiumbicarbonate. The organic layer was separated and the aqueous layer wasextracted with dichloromethane (2×). The combined organic extracts werewashed with brine, dried over sodium sulfate, and concentrated underreduced pressure. The crude product was purified by flash columnchromatography (10 to 40% ethyl acetate in hexanes) to give7-bromo-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline(431 mg, 33%): ¹H NMR (CDCl₃, 500 MHz) δ 7.40 (d, J=2.0 Hz, 1H), 7.36(d, J=8.0 Hz, 1H), 7.22 (dd, J=8.0, 2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H),6.88 (dd, J=8.5, 2.0 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 3.96 (t, J=5.5 Hz,1H), 3.38 (dd, J=13.5, 5.0 Hz, 1H), 3.03 (dd, J=13.5, 5.5 Hz, 1H), 1.51(s, 3H), 1.47 (s, 4H); ESI MS m/z 386 [M+H]⁺.

Step D: To a solution of the product (535 mg, 1.39 mmol) from Step C indimethyl sulfoxide (20 mL), was added bis(pinacolato)diboron (423 mg,1.67 mmol) and potassium acetate (409 mg, 4.17 mmol). The resultantsolution was purged with argon for 10 minutes, and thendichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (114 mg, 0.14 mmol) was added. The reactionsolution was further deoxygenated with argon for 5 minutes and heated at80° C. for 2 hours. The reaction solution was then cooled to roomtemperature, diluted with ethyl acetate, washed with brine, dried oversodium sulfate, and concentrated under reduced pressure to afford theboronate ester (557 mg, crude) which was used in the next step withoutfurther purification: ESI MS m/z 433 [M+H]⁺.

Step E: 3-Trifluoromethyl-6-chloropyridazine (470 mg, 2.57 mmol) wasadded to a mixture of the boronate ester from Step D (557 mg, 1.28mmol), cesium carbonate (1.26 g, 3.87 mmol) in DMF (20 mL), and water (4mL). The reaction mixture was deoxygenated with argon.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (105 mg, 0.128 mmol) was added and the reactionmixture was stirred at 90° C. for 1.5 hours, cooled, diluted with water,and extracted with ethyl acetate (3×). The combined organic extractswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated. Purification by flash column chromatography (0 to 50%90:9:1dichloromethane/methanol/concentrated ammonium hydroxide solutionin dichloromethane) gave the desired trifluoromethylpyridazinyltetrahydro-isoquinoline product (338 mg, 58% over 2 steps): ¹H NMR(CDCl₃, 300 MHz) ¹H NMR (CDCl₃, 500 MHz) δ 8.23 (d, J=2.0 Hz, 1H), 8.01(d, J=9.0 Hz, 1H), 7.87 (dd, J=9.0, 2.5 Hz, 1H), 7.73 (dd, J=8.0, 1.5Hz, 1H), 7.39 (dd, J=8.5, 2.5 Hz, 1H), 7.23 (dd, J=8.5, 2.5 Hz, 1H),7.04 (d, J=8.0, 2.5 Hz, 1H), 6.94 (d, J=8.5, 2.0 Hz, 1H), 4.13 (t, J=5.5Hz, 1H), 3.45 (dd, J=13.5, 5.0 Hz, 1H), 3.10 (dd, J=13.5, 5.5 Hz, 1H),1.66 (s, 1H), 1.57 (s, 3H), 1.55 (s, 3H); ESI MS m/z 453 [M+H]⁺.

Step F: The trifluoromethylpyridazinyl tetrahydro-isoquinoline (153 mg)from Step E was resolved by preparative chiral HPLC (Chiralcel OJcolumn, using 80:20:0.1 heptane/ethanol/diethylamine as the eluent) togive the (−)-enantiomer ([α]²⁵ _(D) −51.0° (c 0.10, methanol)) and the(+)-enantiomer ([α]²⁵ _(D) +33.2° (c 0.10, methanol)).

Example 11 Preparation of4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,L-Tartrate Salt

Step A: To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) inmethanol (1 L) was added a 40% aqueous solution of methylamine (113 ml,1.31 mol) followed by 1 hour stirring at 0° C. Sodium borohydride (75 g,1.98 mol) was added portionwise at 0° C. and the reaction mixture wasstirred for 1 hour. The solution was concentrated to a smaller volumethen, was diluted with water (200 mL) and the resulting solution wasextracted with methylene chloride (3×500 mL). The combined organicextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to afford the crude N-methylbenzylamine (220 g,quantitative) as clear oil, which was used in the next step withoutfurther purification: ¹H NMR (CDCl₃, 500 MHz) δ.7.23 (t, J=8.0 Hz, 1H),6.92-6.88 (m, 2H), 6.81-6.78 (m, 1H), 3.80 (s, 3H), 3.73 (s, 2H), 2.45(s, 3H), 2.07 (broad s, 1H).

Step B: To a solution of the above amine (6.2 g, 41.00 mmol) from Step Ain methylene chloride (100 mL) was added 3,4-dichlorophenacyl bromide(10.0 g, 37.3 mmol) and the resulting mixture was stirred at 0° C. for 1hour prior to the addition of triethylamine (5.20 mL, 37.31 mmol),followed by 1 hour stirring at 0° C. The reaction mixture was dilutedwith water (100 mL) then the aqueous phase was extracted with additionalmethylene chloride (3×75 mL). The combined extracts were dried oversodium sulfate, filtered, and concentrated to afford1-(3,4-dichlorophenyl)-2-(3-methoxybenzyl)(methyl)amino)ethanone (15.08g) as a light yellow oil, which was used in the next step withoutfurther purification: ¹H NMR (500 MHz, CDCl₃) δ 8.08 (d, J=2.0 Hz, 1H),7.78 (dd, J=8.5; 2.0 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz,1H), 6.90 (d, J=7.5 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.82 (dd, J=8.0;2.5 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 2H), 3.60 (s, 2H), 2.33 (s, 3H).

Step C: To a solution of the ketone (˜37 mmol) from Step B in methanol(150 mL), was added sodium borohydride (2.11 g, 55.79 mmol) portionwiseat 0° C. The reaction mixture was first stirred for 2 hours then, wasdiluted with water (100 mL) and extracted with methylene chloride (3×300mL). The combined organic extracts were dried over sodium sulfate,filtered, and concentrated to dryness under reduced pressure to affordthe crude alcohol (14.14 g) as a yellow oil, which was used withoutfurther purification in the next step: ¹H NMR (500 MHz, CDCl₃) δ 7.45(d, J=2.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.16 (dd,J=8.0; 2.0 Hz, 1H), 6.90-6.81 (m, 3H), 4.70-4.65 (m, 1H), 3.81 (s, 3H),3.70 (d, J=13.0 Hz, 1H), 3.50 (d, J=13.0 Hz, 1H), 2.54-2.49 (m, 2H),2.32 (s, 3H).

Step D: To a solution of the alcohol (˜37 mmol) from Step C in methylenechloride (200 mL) was added concentrated sulfuric acid (12 mL, 235 mol)and the mixture was stirred at 0° C. for 28 hours. The reaction wasquenched by adding a 6N NaOH solution till pH˜9. The aqueous phase wasextracted with additional methylene chloride (3×). The combined organicextracts were washed with brine (3×), dried over sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (1:1:1: to 1:1:2 dichloromethane/hexanes/ethyl acetate)to afford4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(7.0 g, 59% over 3 steps) as a light yellow oil: ¹H NMR (500 MHz, CDCl₃)δ 7.33 (d, J=8.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.5; 2.0Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 6.66 (dd, J=8.5; 3.0 hz, 1H), 6.61 (d,J=2.5 Hz, 1H), 4.16-4.11 (m, 1H), 3.77 (s, 3H), 3.67-3.59 (m, 2H), 2.92(dd, J=11.5; 5.5 Hz, 1H), 2.55 (dd, J=11.5; 7.0 Hz, 1H), 2.39 (s, 3H).The undesired 5-methoxy isomer was also isolated (1.20 g, 10% over 3steps).

Step E: The racemic4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(7.0 g) from Step D above was resolved by preparative chiral HPLC(CHIRALPAK AD column, using 80:20:0.1 heptane/2-propanol/diethylamine asthe eluent) to give the (+)-enantiomer ([α]²⁵ _(D) +31.9° (c 0.49,methanol)) (3.68 g) as a colorless oil and the (−)-enantiomer (3.99 g)as a colorless oil.

Step F: A solution of(+)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(3.68 g, 11.42 mmol) in a mixture of acetic acid (20 mL) and 48% aqueoushydrobromic acid solution (50 mL) was refluxed for 8 hours. The ice-coldreaction mixture was basified with a concentrated aqueous solution ofsodium hydroxide and a saturated aqueous solution of sodium bicarbonateuntil reaching a pH of about 8-9 and was extracted with dichloromethane(3×). The combined extracts were dried over sodium sulfate, filtered,and concentrated in vacuo to afford the crude alcohol (2.6 g) as ayellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.32 (d, J=8.5 Hz, 1H), 7.26 (d,J=2.0 Hz, 1H), 7.01 (dd, J=8.0; 2.0 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H),6.54 (d, J=8.5 Hz, 1H), 6.49 (broad s, 1H), 4.15-4.10 (m, 1H), 3.60 (d,J=15.0 Hz, 1H), 3.56 (d, J=15.0 Hz, 1H), 2.96 (dd, J=11.5; 5.7 Hz, 1H),2.52 (dd, J=11.5, 8.0 Hz, 1H), 2.39 (s, 3H).

Step G: To a solution of the phenol from Step F above (2.1 g, 6.81 mmol)and pyridine (0.72 mL, 8.85 mmol) in dichloromethane (60 mL) was addedtrifluoromethanesulfonic anhydride (1.37 mL, 8.14 mmol) at −78° C. Thereaction was allowed to warm to 0° C. and stirred for 1 hour. Thereaction mixture was diluted with water (20 mL) and extracted withdichloromethane (3×). The combined extracts were dried over sodiumsulfate, filtered, and concentrated to give the crude triflate as ayellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J=8.5 Hz, 1H), 7.30 (d,J=2.0 Hz, 1H), 7.03-6.98 (m, 3H), 6.94 (d, J=8.5 Hz, 1H), 4.19-4.15 (m,1H), 3.68 (s, 2H), 2.96 (dd, J=11.7; 5.5 Hz, 1H), 2.60 (dd, J=11.7, 7.5Hz, 1H), 2.42 (s, 3H).

Step H: A mixture of the triflate from Step G above (˜6.8 mmol),bis(pinacolato)diboron (2.07 g, 8.15 mmol), and potassium acetate (2.05g, 20.8 mmol) in dimethyl sulfoxide (35 mL) was degassed with argon. Tothis mixture was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.40 g,0.55 mmol). The resulting mixture was degassed with argon and thenheated at 85° C. for 2 hours. The cold reaction mixture was diluted withethyl acetate (150 mL). The resulting solution was washed with water(2×40 mL), brine (1×40 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. A Purification flash chromatography column(eluent, 1:1:1 to 1:1:2 dichloromethane/hexanes/ethyl acetate) gave thedesired boronate ester (2.6 g, 91% over 2 steps) as a yellow solid. ¹HNMR (500 MHz, CDCl₃) 7.55 (s, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.33 (d,J=8.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H),6.85 (d, J=8.0 Hz, 1H), 4.23 (t, J=6.5 Hz, 1H), 3.71 (d, J=15.0 Hz, 1H),3.67 (d, J=15.0 Hz, 1H), 2.98 (dd, J=11.4, 5.3 Hz, 1H), 2.56 (dd,J=11.4, 7.5 Hz, 1H), 2.41 (s, 3H), 1.33 (s, 12H).

Step I: To a solution of the boronate ester (2.6 g, 6.22 mmol) from StepF and proton sponge (2.6 g, 12.1 mmol) in dichloroethane (80 mL) at 0°C. was added 1-chloroethyl chloroformate (2.4 mL, 22.1 mmol). Themixture was stirred at 0° C. for 15 minutes, then was refluxed for 40minutes and was concentrated in vacuo. The residue was filtered througha short pad of silica gel (eluent, 1:1:1 dichloromethane/hexanes/ethylacetate) and the filtrate was concentrated in vacuo. The residue wasdiluted with methanol (160 mL), heated to reflux for 1 hour andconcentrated in vacuo to give the4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolineas a brown foam.

Step J: A solution of the product from Step I (˜6.2 mmol), (Boc)₂O (3.60g, 16.4 mmol), triethylamine (1.5 mL, 10.7 mmol) and DMAP (0.26 g, 2.20mmol) in dichloromethane (120 mL) was stirred at room temperature for 4hours. The reaction was quenched by the addition of water (50 mL) then,the aqueous phase was extracted with additional dichloromethane (2×100mL). The combined extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo. A purification by flash column chromatography(eluent, 47.5:47.5:5 to 1:1:1 dichloromethane/hexanes/ethyl acetate)gave the boc-protected tetrahydroisoquinoline (1.82 g, 58% over 3 steps)as a white foam. ¹H NMR (500 MHz, CDCl₃) δ 7.65 (s, 1H), 7.58 (d, J=7.5Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.95 (d, J=7.0 Hz, 1H),6.97-6.93 and 6.83-6.78 (m, 1H), 5.01-4.95 and 4.48-4.43 (m, 1H),4.56-4.52 (m, 1H), 3.95 (s, 1H), 3.83-3.44 (m, 2H), 1.43 and 1.26 (2s,9H), 1.33 (s, 12H).

Step K: A dry flask was loaded with the product from Step J above (0.3g, 0.59 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (0.17 g, 0.97mmol), cesium carbonate (0.48 g, 1.47 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (43 mg, 0.058 mmol). The flask was blanketed withargon then, DMF (10 mL) and water (2 mL) were added followed by a shortsonication. The reaction mixture was heated to 80° C. for 2 hours. Thecold reaction mixture was diluted with water (40 mL) and the aqueouslayer was extracted with dichloromethane (3×). The combined organicphases were concentrated in vacuo. Purification by flash columnchromatography (eluent, 47.5:47.5:5 to 45:45:10dichloromethane/hexanes/ethyl acetate) gave the Boc-protected4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(0.30 g, 97%) as a tan solid.

Step L: A solution of the Boc-protected4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(0.29 g, 0.55 mmol) and concentrated hydrochloric acid (1.5 mL) inethanol was stirred at room temperature for 2.5 hours. The precipitatewas isolated by filtration, washed with cold ethanol and hexanes, thendried in a vacuum oven to afford the starting material as an HCl salt.The solid and the filtrate were combined, concentrated in vacuo, anddissolved in a mixture of TFA (˜10 mL) and dichloromethane (20 mL). Thereaction mixture was stirred at room temperature for 1 hour and wasconcentrated in vacuo. The residue was dissolved in dichloromethane (40mL) and treated with a saturated aqueous solution of sodium bicarbonatetill pH˜9. The aqueous phase was extracted with dichloromethane (2×40mL). The extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo. A purification by flash column chromatography(eluent: 98:1.8:0.2 to 96:3.6:0.4 to 90:9:1dichloromethane/methanol/ammonium chloride) gave4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(192 mg, 82%) as a white solid, [[α]²⁵ _(D) +35.3° (c 0.15, methanol)].

Step M: To a solution of4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(176 mg, 0.41 mmol) from Step L in a mixture of methanol and water wasadded L-tartaric acid (62 mg, 0.41 mmol). The solution thus obtained wasfrozen and lyophilized overnight to afford the correspondent L-tartratesalt (196 mg, 81%, AUC HPLC>99%) as a white solid. ¹H NMR (500 MHz,CD₃OD) δ 8.39 (d, J=9.0 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.16 (s, 1H),8.05 (dd, J=8.5; 2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.50 (d, J=2.0 Hz,1H), 7.24 (dd, J=8.5; 2.0 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 4.66-4.61 (m,2H), 4.55 (d, J=16.0 Hz, 1H), 4.41 (s, 2H), 3.80 (dd, J=12.5; 6.0 Hz,1H), 3.49-3.42 (m, 1H). ESI MS m/z 424 [M+H]⁺. Anal. Calcd. ForC₂₀H₁₄Cl₂F₃N₃.C₄H₆O₆.H₂O: C, 48.66; H, 3.74; N, 7.09. Found: C, 48.67;H, 3.7; N, 6.89.

Example 12 Preparation of4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,L-Tartrate Salt

Step A: A dry flask was loaded with the boronate ester (0.3 g, 0.59mmol) from Step J in Example 11, 3-chloro-6-(difluoromethoxy)pyridazine(0.16 g, 0.97 mmol), cesium carbonate (0.48 g, 1.47 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (43 mg,0.058 mmol). The flask was blanketed with argon then, DMF (10 mL) andwater (2 mL) were added followed by a short sonication. The reactionmixture was heated to 80° C. for 2 hours. The cold reaction mixture wasdiluted with water (40 mL) and the aqueous layer was extracted withdichloromethane (3×). The combined organic phases were concentrated invacuo. Purification by flash column chromatography (eluent, 47.5:47.5:5to 45:45:10 dichloromethane/hexanes/ethyl acetate) gave theboc-protected4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(286 mg, 93%) as a white foam.

Step B: A solution of the boc-protected4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(286 mg, 0.54 mmol) and concentrated hydrochloric acid (1.5 mL) inethanol (6 mL) was stirred at room temperature overnight. The reactionmixture was concentrated to dryness in vacuo. The syrup thus obtainedwas diluted with dichloromethane (20 mL) and treated with a saturatedaqueous solution of sodium bicarbonate (˜20 mL) until pH 8-9. Theaqueous phase was extracted with additional dichloromethane (3×40 mL)and the organic phases were dried over sodium sulfate, filtered, andconcentrated in vacuo. A purification by flash column chromatography(eluent, 98:1.8:0.2 to 95:4.5:0.5 to 90:9:10dichloromethane/methanol/ammonium hydroxide) and preparative HPLC gave4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinolin(129 mg, 56%) as a light yellow solid, [[α]²⁵ _(D) +7.8° (c 0.11,methanol)].

Step C: To a solution of the product above (97 mg, 0.23 mmol) from StepB in a mixture of methanol and water was added L-tartaric acid (34 mg,0.23 mmol). The solution thus obtained was frozen and lyophilizedovernight to give4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinolin,L-tartrate (115 mg, 87%, AUC HPLC>99%) as a white solid. ¹H NMR (500MHz, CD₃OD) δ 8.23 (d, J=9.5 Hz, 1H), 7.99 (s, 1H), 7.90-7.88 (m, 1H),7.75 (t, J=72.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.48-7.44 (m, 2H), 7.22(dd, J=8.0; 2.0 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 4.61-4.54 (m, 2H), 4.49(d. J=16.0 Hz, 1H), 4.41 (s, 2H), 3.76 (dd, J=12.5; 6.0 Hz, 1H),3.46-3.40 (m, 1H). ESI MS m/z 422 [M+H]⁺. Anal. Calcd. forC₂₀H₁₅Cl₂F₂N₃O.C₄H₆O₆: C, 50.37; H, 3.70; N, 7.34. Found: C, 50.66; H,3.88; N, 7.36

Example 13 Preparation of4-(3,4-dichlorophenyl)-7-(6-aminopyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

Step A: 3-amino-6-chloropyridazine (420 mg, 3.23 mmol) was added to amixture of4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline(700 mg, 1.68 mmol) which was prepared in Step D of Example 10, cesiumcarbonate (1.58 g, 4.85 mmol) in DMF (50 mL) and water (10 mL). Thereaction mixture was deoxygenated with argon.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (66 mg, 0.081 mmol) was added and the reactionmixture was stirred at 90° C. for 1 hour, cooled, diluted with water,and extracted with dichloromethane (3×). The combined organic extractswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated. Purification by flash column chromatography (0 to 100%90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solutionin dichloromethane) gave4-(3,4-dichlorophenyl)-7-(6-aminopyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline(387 mg, 60% over 2 steps): ¹H NMR (CDCl₃, 500 MHz) ¹H NMR (CDCl₃, 500MHz) δ 8.01 (d, J=2.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.37 (d, J=8.0 Hz,1H), 7.19 (d, J=8.0 Hz, 1H), 6.98-6.90 (m, 2H), 6.82 (d, J=9.0 Hz, 1H),4.74 (s, 2H), 4.07 (t, J=5.5 Hz, 1H), 3.45 (dd, J=13.0, 5.5 Hz, 1H),3.10 (dd, J=13.0, 5.5 Hz, 1H), 1.64 (s, 3H), 1.60 (s, 3H); ESI MS m/z399 [M+H]⁺.

Example 14 Preparation of2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile,trifluoroacetate Salt

Step A: A mixture of4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (100 mg, 0.23 mmol) which was prepared in StepG of Example 11, 2-cyanophenylboronic acid (51 mg, 0.35 mmol) and cesiumcarbonate (225 mg, 0.69 mmol) in water (1 mL) and N,N-dimethylformamide(2 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethaneadduct (8 mg, 0.01 mmol) was added. The mixture was degassed again andthen heated to 90° C. for 3 hours. The mixture was partitioned betweenwater and ethyl acetate (3×) and the combined organic extracts werewashed with brine, dried over sodium sulfate, filtered, andconcentrated. The residue was partially purified by preparativethin-layer chromatography (1:4 hexanes/ethyl acetate) to give2-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile(57 mg, 63%) as a brown solid: ESI MS m/z 393, 395 [M+H]⁺.

Step B: To an ice-cold solution of2-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile(57 mg, 0.14 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(30 mg, 0.14 mmol) in 1,2-dichloroethane (3 mL) was added 1-chlorethylchloroformate (0.03 mL, 0.28 mmol) drop wise. The mixture was stirredfor 15 minutes and then warmed to room temperature overnight. AdditionalN¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (30 mg, 0.14 mmol) and1-chlorethyl chloroformate (0.03 mL, 0.28 mmol) were added at 0° C., themixture stirred 15 minutes, and then heated to reflux for 2 hours. Themixture was cooled to room temperature, concentrated and filteredthrough a pad of silica gel (1:1:1 hexanes/ethylacetate/dichloromethane). The filtrate was concentrated, the residuedissolved in methanol (10 mL) and heated to reflux for 1 hour. Themixture was cooled, concentrated, and purified by semi-preparative HPLCfollowed by lyophilization to give2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile,trifluoroacetate salt (18 mg, 26%) as a brown solid: ¹H NMR (CD₃OD, 500MHz) δ 7.85 (dd, J=7.7, 0.7 Hz, 1H), 7.77-7.73 (m, 1H), 7.60-7.48 (m,6H), 7.25 (dd, J=8.3, 2.1 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.64 (d,J=16.0 Hz, 1H), 4.62 (dd, J=10.7, 6.2 Hz, 1H), 4.54 (d, J=15.7 Hz, 1H),3.84 (dd, J=12.7, 6.1 Hz, 1H), 3.54 (dd, J=12.6, 10.9 Hz, 1H); ESI MSm/z 379 [M+H]⁺.

Example 15 Preparation of3-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile,trifluoroacetate Salt

Following the procedure in Steps A and B of Example 14,4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (100 mg, 0.23 mmol), 3-cyanophenylboronic acid(51 mg, 0.35 mmol), cesium carbonate (225 mg, 0.69 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (8 mg, 0.01 mmol) in N,N-dimethylformamide (2 mL)and water (1 mL) followed by N-de-methylation withN¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (52 mg, 0.24 mmol) and1-chlorethyl chloroformate (0.08 mL, 0.72 mmol) gave3-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile,trifluoroacetate salt (38 mg, 33%, 2 steps) as an off-white solid: ¹HNMR (CD₃OD, 500 MHz) δ 8.01 (d, J=1.5 Hz, 1H), 7.97-7.95 (m, 1H),7.75-7.73 (m, 1H), 7.66-7.63 (m, 2H), 7.60 (dd, J=8.2, 1.7 Hz, 1H), 7.49(d, J=2.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.3, 2.1 Hz, 1H),7.04 (d, J=8.2 Hz, 1H), 4.65-4.52 (m, 3H), 3.83 (dd, J=12.6, 6.1 Hz,1H), 3.51 (dd, J=12.6, 10.8 Hz, 1H); ESI MS m/z 379 [M+H]⁺.

Example 16 Preparation of4-(3,4-dichlorophenyl)-7-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate Salt

Step A: A mixture of4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (300 mg, 0.68 mmol) from Step G of Example 11,4-(methylsulfonyl)phenylboronic acid (176 mg, 0.88 mmol), potassiumbromide (243 mg, 2.04 mmol) and potassium hydroxide (114 mg, 2.04 mmol)in toluene (7 mL) was degassed with argon and thentetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) was added.The mixture was degassed again and then heated to 80° C. for 3 hours.The mixture was cooled to room temperature, diluted withdichloromethane/methanol (9:1), and filtered through a plug of silica.The filtrate was concentrated and the residue partially purified bycolumn chromatography (hexanes to ethyl acetate) to give4-(3,4-dichlorophenyl)-2-methyl-7-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline(72 mg, 24%) as an off-white solid: ESI MS m/z 446 [M+H]⁺.

Step B: To an ice-cold solution of4-(3,4-dichlorophenyl)-2-methyl-7-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline(70 mg, 0.16 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(69 mg, 0.32 mmol) in 1,2-dichloroethane (3 mL) was added 1-chlorethylchloroformate (0.07 mL, 0.64 mmol) drop wise. The mixture was stirredfor 15 minutes and then heated to reflux for 2 hours. The mixture wascooled to room temperature, concentrated, and filtered through a pad ofsilica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtratewas concentrated, the residue dissolved in methanol (10 mL) and heatedto reflux for 1 hour. The mixture was cooled, concentrated, and purifiedby semi-preparative HPLC followed by lyophilization to give4-(3,4-dichlorophenyl)-7-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate salt (58 mg, 66%) as a white solid: ¹H NMR (CD₃OD, 500MHz) δ 8.04 (dd, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 7.68 (s, 1H),7.64 (dd, J=8.2, 1.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.50 (d, J=2.1 Hz,1H), 7.23 (dd, J=8.3, 2.1 Hz, 1H), 7.06 (dd, J=8.2 Hz, 1H), 4.68-4.53(m, 3H), 3.83 (dd, J=12.6, 6.1 Hz, 1H), 3.52 (dd, J=12.5, 10.8 Hz, 1H),3.15 (s, 3H); ESI MS m/z 432 [M+H]⁺.

Example 17 Preparation of1-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one,L-tartrate Salt

Step A: To a mixture of7-bromo-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline(500 mg, 1.35 mmol) which was prepared following similar methoddescribed in Steps A to C of Example 1 starting from2-bromo-1-(3,4-dichlorophenyl)ethanone and1-(3-bromophenyl)-N-methylmethanamine, pyridin-2-ol (154 mg, 1.62 mmol),N,N′-dimethylethylene diamine (58 μl, 0.54 mmol), and potassiumphosphate (572 mg, 2.69 mmol) in 1,4-dioxane (5 mL) was added copper(1)iodide (51 mg, 0.27 mmol). The mixture was degassed with argon and thenheated to 110° C. for 17 hours. The reaction mixture was diluted withwater (20 mL) and extracted with methylene chloride (2×25 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was partially purified by columnchromatography (methylene chloride to 90:9:1 methylenechloride/methanol/ammonium hydroxide) to give1-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one(37 mg, 7%): ESI MS m/z 385 [M+H]⁺.

Step B: A procedure similar to the one in Step B of Example 29 was usedto demethylate1-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one.The desired free base was obtained and a procedure similar to the one inStep C of Example 2 (with the exception of CH₃CN instead of MeOH wasused as the solvent) was used to obtain1-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one,L-tartrate salt (18 mg, 50%) as a white powder: ¹H NMR (CD₃OD, 500 MHz)δ 7.64-7.59 (m, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.35 (s, 1H),7.28-7.23 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 7.07 (d, J=9.0, 1H),6.50-6.48 (m, 1H), 4.55-4.52 (m, 2H), 4.42-4.40 (m, 3.3H), 3.75-3.74 (m,1H), 3.44-3.41 (m, 1H); ESI MS m/z 371 [M+H]⁺.

Example 18 Preparation of2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one,L-tartrate Salt

Step A: A procedure similar to the one in Step A of Example 17 was usedto couple7-bromo-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolinewith pyridazin-3(2H)-one.2-(4-(3,4-Dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-onewas obtained in 23% yield as an off-white foam: ESI MS m/z 386 [M+H]⁺.

Step B: A procedure similar to the one in Step B of Example 29 was usedto demethylate2-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one.The desired free base was obtained and a procedure similar to the one inStep C of Example 2 (with the exception that CH₃CN was used instead ofMeOH as the solvent) was used to obtain2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one,L-tartrate salt (48 mg, 50%) as a white powder: ¹H NMR (CD₃OD, 500 MHz)δ 8.05-8.03 (m, 1H), 7.56-7.54 (m, 2H), 7.50-7.44 (m, 3H), 7.23 (dd,J=8.0, 2.0 Hz, 1H), 7.10 (dd, J=9.5, 1.5 Hz, 1H), 7.03 (d, J=8.5 Hz,1H), 4.56-4.53 (m, 2H), 4.44-4.41 (m, 3.1H), 3.77-3.73 (m, 1H),3.44-3.40 (m, 1H); ESI MS m/z 372 [M+H]⁺.

Example 19 Preparation of4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline

Step A: A mixture of4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(500 mg, 1.1 mmol) which was prepared according to the procedure in StepF of Example 26, 5-bromopyridine (0.21 mL, 2.2 mmol) and cesiumcarbonate (1.08 mg, 3.3 mmol) in water (3 mL) and N,N-dimethylformamide(10 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol)was added. The mixture was degassed again and then heated to 90° C. for2.5 hours. The mixture was partitioned between water and ethyl acetate(3×) and the combined organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated. The residue waspartially purified by column chromatography (9:1 hexanes/ethyl acetateto ethyl acetate, then 90:10:1 methylene chloride/methanol/concentratedammonium hydroxide) to give4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline(282 mg, 65%) as a brown oil: ESI MS m/z 387, 389 [M+H]⁺.

Step B: To an ice-cold solution of4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline(282 mg, 0.73 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(313 mg, 1.46 mmol) in 1,2-dichloroethane (10 mL) was added 1-chlorethylchloroformate (0.32 mL, 1.46 mmol) drop wise. The mixture was stirredfor 15 minutes and then heated to reflux for 2 hours. The mixture wascooled to room temperature, concentrated, and filtered through a pad ofsilica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtratewas concentrated, the residue dissolved in methanol (10 mL), and heatedto reflux for 1 hour. The mixture was cooled, concentrated, neutralizedwith aqueous saturated sodium bicarbonate and ethyl acetate, and thenpurified by column chromatography (methylene chloride to 90:10:1methylene chloride/methanol/concentrated ammonium hydroxide) to give4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolineas yellow oil (13 mg, 5%): ¹H NMR (CDCl₃, 500 MHz) δ 8.72 (d, J=4.7 Hz,1H), 7.77-7.75 (m, 3H), 7.39 (d, J=8.3 Hz, 1H), 7.27-7.24 (m, 2H), 6.99(dd, J=8.3, 2.0 Hz, 1H), 6.68 (d, J=11.9 Hz, 1H), 4.21-4.07 (m, 3H),3.41 (dd, J=12.9, 5.3 Hz, 1H), 3.05 (dd, J=12.9, 6.4 Hz, 1H); ESI MS m/z373 [M+H]⁺.

Example 20 Preparation of4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methylpyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline

Following the procedure in Step A and Step B of Example 19,4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(500 mg, 1.1 mmol), 3-chloro-6-methylpyridazine (282 mg, 2.2 mmol),cesium carbonate (1.08 mg, 3.3 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06mmol) in N,N-dimethylformamide (10 mL) and water (3 mL) followed byN-de-methylation with N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(471 mg, 2.2 mmol) and 1-chlorethyl chloroformate (0.48 mL, 4.4 mmol)gave4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methylpyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(15 mg, 3%, 2 steps) as a green solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.95(d, J=7.8 Hz, 1H), 7.83 (dd, J=8.8, 1.9 Hz, 1H), 7.42-7.35 (m, 3H), 7.00(dd, J=8.3, 1.9 Hz, 1H), 6.70 (d, J=12.0 Hz, 1H), 4.23-4.09 (m, 3H),3.42 (dd, J=12.9, 5.3 Hz, 1H), 3.06 (dd, J=12.9, 6.7 Hz, 1H), 2.77 (s,3H); ESI MS m/z 388, 390 [M+H]⁺.

Example 21 Preparation of4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate Salt

Following the procedure in Step A and Step B of Example 19,4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(500 mg, 1.1 mmol), 3-chloro-6-methoxypyridazine (318 mg, 2.2 mmol),cesium carbonate (1.08 g, 3.3 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06mmol) in N,N-dimethylformamide (10 mL) and water (3 mL) followed byN-de-methylation with N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (26mg, 0.12 mmol) and 1-chlorethyl chloroformate (0.04 mL, 0.36 mmol) gaveafter purification by semi-preparative HPLC and lyophilization4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate salt (33 mg, 6%, 2 steps) as a white solid: ¹H NMR(CD₃OD, 500 MHz) δ 7.95 (dd, J=9.3, 2.1 Hz, 1H), 7.86 (d, J=7.4 Hz, 1H),7.59 (d, J=8.4 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.28-7.25 (m, 2H), 6.82(d, J=11.6 Hz, 1H), 4.63-4.53 (m, 3H), 4.16 (s, 3H), 3.83 (dd, J=12.5,6.2 Hz, 1H), 3.55-3.50 (m, 1H); ESI MS m/z 404 [M+H]⁺.

Example 22 Preparation of 46-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one,trifluoroacetate Salt

A mixture of4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate salt (20 mg, 0.04 mmol, product of Step B in Example21) and hydrobromic acid (aqueous, 48%) was heated to reflux for 1 hour.The mixture was cooled to room temperature and concentrated. The residuewas purified by semi-preparative HPLC followed by lyophilization to give46-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one,trifluoroacetate salt (16 mg, 80%) as a white solid: ¹H NMR (CD₃OD, 500MHz) δ 7.84 (dd, J=9.9, 2.1 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.58 (d,J=8.3 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.24 (dd, J=8.3, 2.0 Hz, 1H),7.04 (d, J=9.9 Hz, 1H), 6.78 (d, J=11.7 Hz, 1H), 4.67-4.49 (m, 3H), 3.81(dd, J=12.6, 6.0 Hz, 1H), 3.50 (dd, J=11.3, 11.3 Hz, 1H); ESI MS m/z 390[M+H]⁺.

Example 23 Preparation of4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline

Following the procedure of Step A and Step B of Example 19,4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(500 mg, 1.1 mmol), 1-bromo-3-(methylsulfonyl)benzene (517 mg, 2.2mmol), cesium carbonate (1.08 g, 3.3 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06mmol) in N,N-dimethylformamide (10 mL) and water (3 mL) followed byN-de-methylation with N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(240 mg, 1.12 mmol) and 1-chlorethyl chloroformate (0.31 mL, 2.8 mmol)gave after purification by preparative HPLC followed by preparative thinlayer chromatography (90:10:1 diethyl ether/methanol/concentratedammonium hydroxide)4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline(38 mg, 15%) as a colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ 8.10 (s, 1H),7.94 (d, J=7.5 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.65 (dd, J=8.0, 8.0 Hz,1H), 7.41 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.01(dd, J=8.0, 2.0 Hz, 1H), 6.71 (d, J=11.0 Hz, 1H), 4.20-4.09 (m, 3H),3.43 (dd, J=13.0, 5.5 Hz, 1H), 3.10 (s, 3H), 3.07 (dd, J=13.0, 6.5 Hz,1H), 2.04 (br s, 1H); ESI MS m/z 450 [M+H]⁺

Example 24 Preparation of4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide

Step A: To an ice-cold solution of4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (1.0 g, 2.3 mmol) andN¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (493 mg, 2.3 mmol) in1,2-dichloroethane (25 mL) was added 1-chlorethyl chloroformate (0.75mL, 6.9 mmol) drop wise. The mixture was heated to reflux for 1 hour.The mixture was cooled to room temperature, concentrated, and filteredthrough a pad of silica gel (1:1:1 hexanes/ethylacetate/dichloromethane). The filtrate was concentrated, the residuedissolved in methanol (50 mL), and then heated to reflux for 1 hour. Themixture was cooled, concentrated, neutralized with aqueous saturatedsodium bicarbonate and ethyl acetate, and then purified by columnchromatography (hexanes to ethyl acetate) to give4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (455 mg, 46%) as a brown oil: ESI MS m/z 426[M+H]⁺.

Step B: A mixture of4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (225 mg, 0.53 mmol), 4-carbamoylphenylboronicacid (132 mg, 0.8 mmol) and cesium carbonate (521 mg, 1.6 mmol) in water(2 mL) and N,N-dimethylformamide (4 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol)was added. The mixture was degassed again and then heated to 90° C. for2 hours. The mixture was partitioned between water and ethyl acetate(3×) and the combined organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated. The residue waspurified by semi-preparative HPLC followed by lyophilization to give4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(19 mg, 7%) as a yellow oil: ¹H NMR (CD₃OD, 500 MHz) δ 7.96 (d, J=8.3Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.64 (s, 1H), 7.62-7.59 (m, 1H), 7.56(d, J=8.3 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz, 1H),7.02 (d, J=8.2 Hz, 1H), 4.67-4.53 (m, 3H), 3.82 (dd, J=12.6, 6.1 Hz,1H), 3.51 (dd, J=12.5, 10.9 Hz, 1H); ESI MS m/z 397 [M+H]⁺.

Example 25 Preparation of4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dimethylisoxazole

Following the procedure in Example 24,4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (225 mg, 0.53 mmol),3,5-dimethylisoxazol-4-ylboronic acid (114 mg, 0.8 mmol), cesiumcarbonate (521 mg, 1.6 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03mmol) in N,N-dimethylformamide (4 mL) and water (2 mL) gave4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dimethylisoxazole(95 mg, 48%) as a brown oil: ¹H NMR (CD₃OD, 500 MHz) δ 7.46 (d, J=8.3Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.13-7.08 (m, 3H), 6.92 (d, J=8.0 Hz,1H), 4.24-4.05 (m, 3H), 3.39 (dd, J=12.9, 5.7 Hz, 1H), 3.01 (dd, J=12.9,8.3 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H); ESI MS m/z 373 [M+H]⁺.

Example 26 Preparation of4-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide,L-tartrate Salt

Step A: To a solution of1-(4-fluoro-3-methoxyphenyl)-N-methylmethanamine (0.9 g, 5.39 mmol) inethanol (8.0 mL) was added potassium carbonate (0.6 g, 4.48 mmol) and2-bromo-1-(3,4-dichlorophenyl)ethanone (1.2 g, 4.48 mmol). The reactionsolution was stirred for 2.5 hours at room temperature and then sodiumborohydride (0.2 g, 5.83 mmol) was added to it portionwise at 0° C. Thereaction mixture was stirred overnight while warming up to roomtemperature. The reaction solution was concentrated in vacuo. The slurryobtained was quenched with water and extracted with methylene chloride.The combined organic extracts were washed with brine (2×200 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by flash column chromatography (1:1 to1:9 hexanes/ethyl acetate) to afford1-(3,4-dichlorophenyl)-2-(4-fluoro-3-methoxybenzyl)(methyl)amino)ethanol(1.9 g): ¹H NMR (CDCl₃, 300 MHz) δ 7.45 (d, J=1.5 Hz, 1H), 7.39 (d,J=3.0 Hz, 1H), 7.16 (dd, J=8.0, 2.0 Hz, 1H), 7.05-7.01 (m, 1H), 6.91(dd, J=8.0, 2.0 Hz, 1H), 6.81-6.78 (m, 1H), 4.69 (t, J=7.0 Hz, 1H), 3.98(br.s, 1H), 3.90 (s, 3H), 3.67 (d, J=13.5 Hz, 1H), 3.47 (d, J=13.0 Hz,1H), 2.50 (d, J=7.0 Hz, 2H), 2.32 (s, 3H); ESI MS m/z 358 [M+H]⁺.

Step B: To a solution of the alcohol (1.1 g, 2.93 mmol) from Step Aabove in methylene chloride (10.0 mL) was added concentrated sulfuricacid (1.5 mL, 0.56 mmol). The reaction mixture was stirred at 0° C. for30 minutes and at room temperature for 2 hours. The reaction solutionwas quenched at 0° C. by addition of an aqueous solution of sodiumhydroxide (2N) and the aqueous phase was extracted with additionalmethylene chloride (3×). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography (7:3 to 1:9 hexanes/ethylacetate) to afford4-(3,4-dichlorophenyl)-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(1.0 g, 98%): ¹H NMR (500 MHz, CDCl₃) δ 7.35 (d, J=8.0 Hz, 1H), 7.28 (d,J=2.5 Hz, 1H), 7.03 (dd, J=8.0, 2.0 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H),6.55 (d, J=12.0 Hz, 1H), 4.09 (t, J=7.5 Hz, 1H), 3.87 (s, 3H), 3.60 (s,2H), 2.92 (dd, J=12.0, 5.5 Hz, 1H), 2.53 (dd, J=11.5, 7.5 Hz, 1H), 2.41(s, 3H); ESI MS m/z 340 [M+H]⁺.

Step C: The racemic 7-methoxy tetrahydroisoquinole from Step B above(8.5 g) was resolved by preparative chiral HPLC (CHIRALPAK AD column,using 80:20:0.1 heptane/isopropanol/diethylamine as the eluent) to give(+) enantiomer (4.0 g) and (−) enantiomer (4.0 g).

Step D: To a solution of (+) 7-methoxytetrahydroisoquinoline from Step Cabove (3.4 g, 11.70 mmol) in hydrobromic acid (90 mL, 48% solution inwater) was added acetic acid (48 mL). The reaction solution was stirredat 110° C. overnight under nitrogen and then concentrated under reducedpressure. The resultant solution was quenched with sodium bicarbonateand extracted with dichloromethane, dried over aqueous sodium sulfate,and concentrated under reduced pressure to give the desired phenol (3.6g, crude), which was used in the next step without further purification:¹H NMR (MeOD, 500 MHz) δ 7.44 (d, J=7.0 Hz, 1H), 7.33 (d, J=1.5 Hz, 1H),7.11 (dd, J=8.0, 2.0 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.46 (d, J=12.0Hz, 1H), 4.19 (t, J=7.0 Hz, 1H), 3.67-3.53 (m, 2H), 3.01 (dd, J=11.5,5.5 Hz, 1H), 2.52 (dd, J=12.0, 9.0 Hz, 1H), 2.40 (s, 3H); ESI MS m/z 326[M+H]⁺.

Step E: To a solution of the phenol (2.5 g, 7.79 mmol) from Step D abovein dichloromethane (30 mL) at 0° C. was added pyridine (0.8 mL, 10.12mmol) followed by slow addition of trifluoromethanesulfonic anhydride(1.4 mL, 8.18 mmol) dropwise. The resultant reaction solution wasstirred at 0° C. for 1 hour, and then was quenched with aqueoussaturated sodium bicarbonate. The organic extract was separated and theaqueous layer was extracted with dichloromethane (3×). The combinedorganic extract was washed with 1:1 water/brine, dried over sodiumsulfate, and concentrated under reduced pressure to give the desiredtriflate (3.5 g) as a yellow oil: ¹H NMR (CDCl₃, 500 MHz) δ 7.39 (dd,J=8.0, 2.5 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.02(dd, J=6.0, 2.0 Hz, 1H), 6.75 (d, J=10.0 Hz, 1H), 4.14 (t, J=6.5 Hz,1H), 3.61 (s, 2H), 2.95 (dd, J=11.5, 5.5 Hz, 1H), 2.58 (dd, J=11.5, 7.0Hz, 1H), 2.43 (s, 3H).

Step F: To a mixture of triflate (3.5 g, 7.57 mmol) in Step E abovebis(pinacolato)diboron (2.3 g, 9.09 mmol) and potassium acetate (2.2 g,22.72 mmol) were added in DMSO (100.0 mL). The reaction solution waspurged with argon for 10 minutes, and then1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (0.5 g, 0.61 mmol)was added to it. The reaction solution was degassed again with argon for5 minutes and heated at 80° C. overnight. The reaction solution was thencooled to room temperature, diluted with ethyl acetate, washed withsaturated aqueous sodium bicarbonate, dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained waspurified by flash column chromatography (90:9:1dichloromethane/methanol/concentrated ammonia) to give the desiredboronate ester (0.1 g, 3%): ¹H NMR (CDCl₃, 500 MHz) δ 7.48 (d, J=6.0 Hz,1H), 7.37-7.34 (m, 1H), 7.27 (s, 1H), 7.00 (dd, J=8.0, 2.0 Hz, 1H),6.56-6.51 (m, 1H), 4.19 (t, J=6.5 Hz, 1H), 3.69-3.53 (m, 2H), 2.96 (dd,J=11.5, 5.5 Hz, 1H), 2.53 (dd, J=11.5, 7.5 Hz, 1H), 2.40 (s, 3H), 1.35(s, 12H).

Step G: A mixture of4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(1.0 g mg, 2.3 mmol), 4-bromobenzamide (690 mg, 3.45 mmol) and cesiumcarbonate (2.25 g, 6.9 mmol) in water (6 mL) and N,N-dimethylformamide(20 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (88 mg, 0.12 mmol)was added. The mixture was degassed again and then heated to 90° C. for2 hours. The mixture was partitioned between water and ethyl acetate(3×) and the combined organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated. The residue waspartially purified by column chromatography (7:3 hexanes/ethyl acetateto ethyl acetate, then ethyl acetate to 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to give4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(423 mg, 43%) as a brown solid: ESI MS m/z 429 [M+H]⁺.

Step H: A mixture of4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(490 mg, 1.1 mmol), di-tert-butyl dicarbonate (1.2 g, 0.65 mmol) and4-dimethylaminopyridine (13 mg, 0.11 mmol) in dichloromethane (5 mL) wasstirred at room temperature overnight and then concentrated.Purification by column chromatography (hexanes to 1:1 hexanes/ethylacetate) gave bis-Boc protected4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(59 mg, 76%) as a light yellow oil: ESI MS m/z 628 [M+H]⁺.

Step I: To an ice-cold solution of bis-Boc protected4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(515 mg, 0.82 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(527 mg, 2.46 mmol) in 1,2-dichloroethane (15 mL) was added 1-chlorethylchloroformate (0.27 mL, 2.46 mmol) drop wise. The mixture was stirredfor 15 minutes and then heated to 40° C. for 2 hours. The mixture wasconcentrated and filtered through a pad of silica gel (1:1:1hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated,the residue dissolved in methanol (5 mL) and heated to reflux for 1 hourand then concentrated. The residue was dissolved in dichloromethane (5mL) and trifluoroacetic acid (5 mL), stirred for 2 hours, concentratedand purified by semi-preparative HPLC, and neutralized with saturatedsodium bicarbonate and ethyl acetate to give4-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamideas an off-white solid (95 mg, 28%). A mixture of4-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(20 mg, 0.05 mmol) and L-tartaric acid (7 mg, 0.05 mmol) in acetonitrileand water was lyophilized to give4-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide,L-tartrate salt (29 mg, 100%): ¹H NMR (CD₃OD, 500 MHz) δ 7.96 (dd,J=6.5, 2.0 Hz, 2H), 7.67-7.65 (m, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.51 (d,J=2.0 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.24 (dd, J=8.5, 2.5 Hz, 1H),6.73 (d, J=11.5 Hz, 1H), 4.58-4.44 (m, 3H), 4.43 (s, 2.6H), 3.80-3.75(m, 1H), 3.45-3.40 (m, 1H); ESI MS m/z 415 [M+H]⁺.

Example 27 Preparation of5-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine,trifluoroacetate Salt

Step A: To an ice-cold solution of4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(3.46 g, 10.7 mmol, prepared in Step D of Example 11) andN¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (2.3 g, 10.7 mmol) in1,2-dichloroethane (70 mL) was added 1-chlorethyl chloroformate (2.4 mL,21.4 mmol) drop wise. The mixture was stirred for 15 minutes and thenheated to reflux for 1 hour. The mixture was cooled to room temperature,concentrated and then filtered through a pad of silica gel (1:1:1hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated,the residue dissolved in methanol (100 mL) and heated to reflux for 1hour. The mixture was cooled, concentrated, and the residue neutralizedwith ethyl acetate and saturated aqueous sodium bicarbonate to give4-(3,4-dichlorophenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.65 g,80%) as a brown oil: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.53 (d, J=8.3 Hz, 1H),7.41 (d, J=2 Hz, 1H), 7.15 (dd, J=8.3, 2 Hz, 1H), 9.71-6.67 (m, 3H),4.07-4.00 (m, 2H), 3.91 (m, 1H), 3.72 (s, 3H), 3.22 (dd, J=12.5, 5.3 Hz,1H), 2.92 (dd, J=12.5, 6.5 Hz, 1H).

Step B: To an ice-cold solution of4-(3,4-dichlorophenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.65 g,8.6 mmol) and N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) indichloromethane (80 mL) was slowly added a solution of2-nitrobenzene-1-sulfonyl chloride (2.1 g, 9.5 mmol) in dichloromethane(10 mL). The mixture was stirred for 2 hours and then quenched withwater. The organic layer was washed with brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by columnchromatography (hexanes to ethyl acetate) to give4-(3,4-dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline(3.39 g, 80%) as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.80 (dd,J=8, 1.3 Hz, 1H), 7.67-7.63 (m, 1H), 7.58 (dd, J=7.9, 1.2 Hz, 1H),7.54-7.50 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.87(dd, J=8.3, 2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H),6.73 (s, 1H), 4.77 (d, J=16.0 Hz, 1H), 4.56 (d, J=16.0 Hz, 1H), 4.18(dd, J=4.9, 4.9 Hz, 1H), 3.82 (dd, J=13.2, 4.5 Hz, 1H), 3.81 (s, 3H),3.63 (dd, J=13.1, 5.5 Hz, 1H).

Step C: To a −78° C. solution of4-(3,4-dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline(3.39 g, 6.88 mmol) in dichloromethane (70 mL) was added borontribromide (3.25 mL, 34.4 mmol) drop wise. The mixture was stirred for 5minutes and then warmed to 0° C. for 1 hour. The mixture was quenchedwith water slowly and then the aqueous layer was extracted withdichlormethane (2×). The combined organic layers were dried over sodiumsulfate, filtered and concentrated to give4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-ol(3.25 g, 98%) as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.80 (dd,J=8.0, 1.2 Hz, 1H), 7.67-7.63 (m, 1H), 7.58 (dd, J=7.9, 1.2 Hz, 1H),7.54-7.50 (m, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.02 (d, J=2 Hz, 1H), 6.86(dd, J=8.3, 2 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.68-6.65 (m, 2H), 4.88(s, 1H), 4.74 (d, J=16.2 Hz, 1H), 4.53 (d, J=16.1 Hz, 1H), 4.16 (dd,J=4.9, 4.9 Hz, 1H), 3.83 (dd, J=13.2, 4.5 Hz, 1H), 3.62 (dd, J=13.1, 5.5Hz, 1H).

Step D: To a −20° C. solution of4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-ol(2.0 g, 4.18 mmol) and pyridine (0.37 mL, 4.6 mmol) in dichloromethane(40 mL) was added trifluoromethanesulfonic acid anhydride (0.77 mL, 4.6mmol) drop wise. The mixture was stirred for 3 hours and then quenchedwith saturated aqueous sodium bicarbonate. The organic layer was washedwith brine, dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by column chromatography (hexanes to 1:1hexanes/ethyl acetate) to give4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (2.03 g, 80%) as an off-white solid: ¹H NMR(CDCl₃, 500 MHz) δ 7.86 (dd, J=8.0, 1.3 Hz, 1H), 7.71-7.67 (m, 1H),7.63-7.56 (m, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.10(dd, J=8.6, 2.6 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H),6.86 (dd, J=8.3, 2.2 Hz, 1H), 4.80 (d, J=16.5 Hz, 1H), 4.64 (d, J=16.5Hz, 1H), 4.27 (dd, J=5.2, 5.2 Hz, 1H), 3.90 (dd, J=13.3, 4.7 Hz, 1H),3.62 (dd J=13.4, 6.2 Hz, 1H).

Step E: A mixture of4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (2.0 g, 3.27 mmol), bis(pinacolato)diboron(914 mg, 3.6 mmol) and potassium acetate (963 mg, 9.81 mmol) in dimethylsulfoxide (15 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethaneadduct (131 mg, 0.16 mmol) was added. The mixture was degassed again andthen heated to 80° C. for 2.5 hours. The mixture was partitioned betweenwater and ethyl acetate (3×) and the combined organic extracts werewashed with brine, dried over sodium sulfate, filtered, and concentratedto give4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolineas a brown oil that was used without purification: ESI MS m/z 589[M+H]⁺.

Step F: A mixture of4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(300 mg, 0.51 mmol), 5-bromopyrazin-2-amine (174 mg, 1.0 mmol) andcesium carbonate (490 mg, 1.5 mmol) in water (1.5 mL) andN,N-dimethylformamide (5 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethaneadduct (24 mg, 0.03 mmol) was added. The mixture was degassed again andthen heated to 90° C. for 3 hours. The mixture was partitioned betweenwater and ethyl acetate (3×) and the combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was partially purified by column chromatography (9:1hexanes/ethyl acetate to ethyl acetate) to give5-(4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine(40 mg, 14%) as a yellow oil: ESI MS m/z 556 [M+H]⁺.

Step G:5-(4-(3,4-Dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine(40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and ethanol(2 mL). Thiophenol (0.04 mL, 0.35 mmol) and potassium carbonate (77 mg,0.56 mmol) were added and the mixture stirred overnight at roomtemperature. The mixture was filtered and concentrated. The residue waspurified by semi-preparative HPLC twice followed by lyophilization togive5-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine,trifluoroacetate salt (14 mg, 40%) as a yellow solid: ¹H NMR (CD₃OD, 500MHz) δ 8.36 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.78 (d, J=7.8 Hz, 1H),7.56 (d, J=8.2 Hz, 1H), 7.48 (s, 1H), 7.23-7.21 (m, 1H), 6.99 (d, J=8.0Hz, 1H), 4.64-4.50 (m, 3H), 3.81 (dd, J=12.5, 6.0 Hz, 1H), 3.52-3.47 (m,1H); ESI MS m/z 371 [M+H]⁺.

Example 28 Preparation of6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine,trifluoroacetate Salt

Following the procedure in Step F and Step G in Example 27,4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(300 mg, 0.51 mmol), 6-chloropyrazin-2-amine (129 mg, 1.0 mmol), cesiumcarbonate (490 mg, 1.5 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (24 mg, 0.03 mmol) in N,N-dimethylformamide (5mL) and water (1.5 mL) followed by deprotection with thiophenol (0.02mL, 0.2 mmol) and potassium carbonate (44 mg, 0.32 mmol) gave6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine,trifluoroacetate salt (9 mg, 5%, 2 steps) as a yellow solid: ¹H NMR(CD₃OD, 500 MHz) δ 8.22 (br s, 1H), 7.95 (s, 1H), 7.90-7.88 (m, 2H),7.56 (d, J=8.3 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz,1H), 7.01 (d, J=8.2 Hz, 1H), 4.66-4.51 (m, 3H), 3.82 (dd, J=12.7, 6.3Hz, 1H), 3.54-3.49 (m, 1H); ESI MS m/z 371, 373 [M+H]⁺.

Example 29 Preparation of(+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,L-tartrate Salt

Step A: A mixture of(+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(350 mg, 0.80 mmol, prepared in Step F in Example 26),3-chloro-6-(trifluoromethyl)pyridazine (176 mg, 0.96 mmol) and cesiumcarbonate (786 mg, 2.41 mmol), in water (0.8 mL) andN,N-dimethylformamide (4 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethaneadduct (33 mg, 0.04 mmol) was added. The mixture was degassed again andthen heated to 90° C. for 2.5 hours. The reaction mixture was dilutedwith ethyl acetate (30 mL), washed with water (2×10 mL), brine (10 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was partially purified by column chromatography (methylenechloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) togive(+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(373 mg, 28%) as a brown oil: ESI MS m/z 456 [M+H]⁺.

Step B: To(+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(320 mg, 0.70 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(299 mg, 0.70 mmol) in 1,2-dichloroethane (5 mL) was added 1-chlorethylchloroformate (0.15 mL, 1.4 mmol) drop wise. The mixture was heated toreflux for 3 hours and then cooled to ambient temperature. The reactionmixture was diluted with methylene chloride (30 mL) and washed with 1NHCl (10 mL), water (10 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. To the residue was added methanol (15 mL) and themixture was heated to reflux. After 1 hour, the reaction mixture wascooled to ambient temperature and concentrated under reduced pressure.The residue was taken up in ethyl acetate (30 mL) and washed withsaturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography (methylene chloride to90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparativeTLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To theobtained material in acetonitrile (1.5 mL) was added L-tartaric acid(9.2 mg, 0.06 mmol) in water (5 mL). The resultant solution waslyophilized to give(+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,L-tartrate salt (47 mg, 11%) as a white powder: ¹H NMR (CD₃OD, 500 MHz)δ 8.32 (d, J=8.5 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.07 (d, J=7.0 Hz,1H), 7.57 (d, J=8.0 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.24 (dd, J=8.5,2.0 Hz, 1H), 6.85 (d, J=11.5 Hz, 1H), 4.59-4.48 (m, 3H), 4.41 (s, 1.8H),3.77-3.71 (m, 1H), 3.40-3.38 (m, 1H); ESI MS m/z 442 [M+H]⁺.

Example 30 Preparation of4-(4-(4-chlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide,trifluoroacetate Salt

Step A: A mixture of4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yltrifluoromethanesulfonate (695 mg, 1.64 mmol) which was prepared usingsimilar methods described in Step A to Step E of Example 26 startingfrom 2-bromo-1-(4-chlorophenyl)ethanone, 4-carbamoylphenylboronic acid(406 mg, 2.46 mmol) and cesium carbonate (1.6 mg, 4.92 mmol) in water (5mL) and N,N-dimethylformamide (20 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (59 mg, 0.08 mmol)was added. The mixture was degassed again and then heated to 90° C. for2 hours. The mixture was partitioned between water and ethyl acetate(3×) and the combined organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated. The residue waspurified by preparative HPLC followed by preparative thin-layerchromatography (90:10:1 diethyl ether/methanol/concentrated ammoniumhydroxide) to give4-(4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(204 mg, 32%) as an off-white solid: ESI MS m/z 395 [M+H]⁺.

Step B: A mixture of4-(4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(50 mg, 0.13 mmol), di-tert-butyl dicarbonate (142 mg, 0.65 mmol) and4-dimethylaminopyridine (1 mg, 0.01 mmol) in dichloromethane (1 mL) wasstirred at room temperature overnight and then concentrated.Purification by preparative thin-layer chromatography (1:1 hexanes/ethylacetate) gave bis-Boc protected4-(4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(59 mg, 76%) as a light yellow oil: ESI MS m/z 596 [M+H]⁺.

Step C: To an ice-cold solution of bis-Boc protected4-(4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide(59 mg, 0.10 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine(64 mg, 0.30 mmol) in 1,2-dichloroethane (2 mL) was added 1-chlorethylchloroformate (0.03 mL, 0.30 mmol) drop wise. The mixture was stirredfor 15 minutes and then heated to 40° C. for 1 hour. The mixture wasconcentrated and filtered through a pad of silica gel (1:1:1hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated,the residue dissolved in methanol (5 mL) and heated to reflux for 30minutes and then concentrated. The residue was dissolved indichloromethane (1 mL) and trifluoroacetic acid (1 mL), stirred for 2hours, concentrated, and purified by semi-preparative HPLC followed bylyophilization to give4-(4-(4-chlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide,trifluoroacetate salt (12 mg, 24%) as an off-white solid: ¹H NMR (CD₃OD,500 MHz) δ 7.96 (dd, J=6.5, 1.5 Hz, 2H), 7.65 (dd, J=8.0, 1.5 Hz, 2H),7.51 (d, J=8.0 Hz, 1H), 7.45 (dd, J=6.5, 2.0 Hz, 2H), 7.30 (dd, J=7.0,2.0 Hz, 2H), 6.73 (d, J=11.5 Hz, 1H), 4.61-4.50 (m, 3H), 3.83-3.79 (m,1H), 3.51-3.46 (m, 1H); ESI MS m/z 381 [M+H]⁺.

Example 31 Preparation of(+)-4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline,L-tartrate salt

Step A: A procedure similar to the one in Step A of Example 29 was usedto couple(+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolinewith 3-chloro-6-(difluoromethoxy)pyridazine.(+)-4-(3,4-Dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolinewas obtained in 66% yield as a brown oil: ESI MS m/z 454 [M+H]⁺.

Step B: A procedure similar to the one in Step B of Example 29 was usedto demethylate(+)-4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline.The desired free base was obtained and a procedure similar to the one inStep C of Example 2 was used to obtain(+)-4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline,L-tartrate (70 mg, 24%) as a white powder: ¹H NMR (CD₃OD, 500 MHz) δ8.13 (dd, J=9.5, 1.5 Hz, 1H), 7.89 (d J=7.5 Hz, 1H), 7.77 (t, J=72 Hz,1H), 7.57 (d, J=8.0 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.47 (d, J=9.5 Hz,1H), 7.25 (dd, J=8.5, 2.0 Hz, 1H), 6.80 (d, J=11.5 Hz, 1H), 4.62-4.51(m, 3H), 4.43 (s, 2.25H), 3.80-3.76 (m, 1H), 3.45-3.41 (m, 1H); ESI MSm/z 440 [M+H]⁺.

Example 32 Preparation of(+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline

Step A: A procedure similar to the one in Step A of Example 29 was usedto couple(+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolinewith 2-chloropyrazine.(+)-4-(3,4-Dichlorophenyl)-6-fluoro-2-methyl-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolinewas obtained in 47% yield as a brown oil: ESI MS m/z 388 [M+H]⁺.

Step B: A procedure similar to the one in Step B of Example 29 was usedto demethylate(+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolineto obtain(+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline(15 mg, 7%) as a yellow residue: ¹H NMR (CDCl₃, 500 MHz) δ 9.07 (s, 1H),8.67 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H),7.42 (d, J=8.5 Hz, 1H), 7.28-7.27 (m, 2H), 7.02 (dd, J=8.5, 2.0 Hz, 1H),6.72 (d, J=11.5 Hz, 1H), 4.30-4.28 (m, 3H), 3.56-3.53 (m, 1H), 3.13-3.08(m, 1H); ESI MS m/z 374 [M+H]⁺.

Example 33 Preparation of4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline,tartrate Salt

Step A: A mixture of tert-butyl4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(332 mg, 0.66 mmol) from Step H in Example 11,3,6-dichloropyridazine(149 mg, 0.90 mmol), cesium carbonate (860 mg, 2.64 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27 mg, 0.03mmol) was taken up in DMF (2.5 mL) and water (0.5 mL). The reactionflask was purged with nitrogen and heated at 80° C. for 6 hours. Thereaction mixture was cooled to ambient temperature then partitionedbetween ethyl acetate (100 mL) and water (100 mL). The organic layer waswashed with water and brine then dried over sodium sulfate.Concentration in vacuo and purification by flash column chromatography(80:20 to 20:80 hexanes/ethyl acetate) gave tert-butyl7-(6-chloropyridazin-3-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(259 mg, 79%) as a brown solid: ¹H NMR (CDCl₃, 300 MHz) δ 7.95-7.70 (m,1H), 7.81 (d, 2H), 7.58 (d, 1H), 7.36 (d, 1H), 7.19 (s, 1H), 7.12 (d,1H), 7.02-6.85 (m, 1H), 5.12-4.55 (m, 2H), 4.20-4.15 (m, 1H), 4.07-3.85(m, 1H), 3.78-3.66 (m, 1H), 1.45 (s, 3H), 1.24 (s, 6H); ESI MS m/z 490[M+H]⁺.

Step B: To a solution of tert-butyl7-(6-chloropyridazin-3-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(259 mg, 0.52 mmol) in ethanol (15 mL) was added 10% palladium on carbon(80 mg) and hydrazine hydrate (128 mL, 2.60 mmol). The reaction mixturewas heated at 75° C. for 1 hour under a nitrogen atmosphere. Anadditional quantity of hydrazine hydrate (128 mL, 2.60 mmol) was addedand the reaction mixture heated at 75° C. for 3 hours 10% palladium oncarbon (80 mg) was additionally added and the heating continued foranother 2 hours. The reaction mixture was filtered through a celite padand the filtrate concentrated in vacuo. The residue was dissolved indichloromethane (5 mL) and treated with trifluoroacetic acid (10 mL) atambient temperature for 1 hour. After concentration in vacuo the residuewas partitioned between dichloromethane (50 mL) and 2N sodium hydroxidesolution. The organic layer was washed with brine then dried over sodiumsulfate. Concentration in vacuo gave the crude material which waspurified by flash column chromatography ((95:5 to 50:50 ethylacetate/ethyl acetate:methanol:ammonium hydroxide, 80:18:2 v/v) to give4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(144 mg, 77%): [α]^(D)=+19.2° (0.06, methanol): ¹H NMR (CDCl₃, 300 MHz)δ 9.15 (dd, J=5.0 Hz, 1.5 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 7.85 (dd,J=8.5 Hz, 1.5 Hz, 1H), 7.77 (dd, J=8.3 Hz, 2.0 Hz, 1H), 7.54 (d, J=8.5Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 6.99 (dd, J=8.3 Hz, 2.0 Hz, 1H), 4.15-4.11 (m, 3H), 3.44 (dd,J=12.8 Hz, 5.5 Hz, 1H), 3.10 (dd, J=13.0 Hz, 6.0 Hz, 1H), 1.95 (br s,1H); ESI MS m/z 356 [M+H]⁺.

Step C: To a solution of4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(135 mg, 0.38 mmol) in methanol (2.5 mL) was added L-tartaric acid (57mg, 0.38 mmol). The mixture was sonicated for 5 minutes, diluted withwater (15 mL), and lyophilized to give the correspondent, L-tartratesalt (96 mg, 45%, AUC HPLC 98.6%) as a white solid. ¹H NMR (CD₃OD, 500MHz) δ 9.16 (dd, J=5.0 Hz, 1.5 Hz, 1H), 8.19 (dd, J=8.8 Hz, 1.0 Hz, 1H),8.06 (s, 1H), 7.95 (dd, J=8.0 Hz, 1.5 Hz, 1H), 7.80 (dd, J=9.0 Hz, 5.0Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.25 (dd, J=8.5Hz, 2.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.65-4.54 (m, 3H), 4.43-4.41(m, 2H), 3.81 (dd, J=12.3 Hz, 5.5 Hz, 1H), 3.47 (t, J=12.5 Hz, 1H); ESIMS m/z 356 [M+H]⁺. Anal. calcd. C₁₉H₁₅Cl₂N₃.1.2C₄H₆O₆.1.5H₂O: C, 50.74;H, 4.51; N, 7.46.

Found C, 50.64; H, 4.36; N, 7.47.

Example 34 Preparation of6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine,tartrate Salt

6-(4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine(64 mg, 0.19 mmol) in methanol (3 mL) was prepared using similar methodsdescribed in Step K to Step L in Example 11 starting with tert-butyl4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateand 6-chloropyridazin-3-amine. The L-tartrate salt was prepared as awhite solid. ¹H NMR (CD₃CO₂D, 300 MHz) δ 7.87 (s, 1H), 7.76 (d, J=9.6Hz, 2H), 7.33-7.28 (m, 1H), 7.30 (dd, J=8.7 Hz, 5.4 Hz, 1H), 7.13 (t,J=8.7 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 6.97 (d, J=9.3 Hz, 1H), 4.65-4.54(m, 3H), 4.42 (s, 2H), 3.78 (dd, J=12.6 Hz, 5.7 Hz, 1H), 3.45 (t, J=11.1Hz, 1H), 3.01 (s, 3H); ESI MS m/z 371 [M+H]⁺. Anal. calcd.C₁₉H₁₆Cl₂N₄.1.2C₄H₆O₆.1.75H₂O: C, 49.04; H, 4.62; N, 9.61. found C,49.07; H, 4.65; N, 9.45.

Example 35 Preparation of (+)- and(−)-4-(4-chlorophenyl)-7-(6-trifluoromethyl-pyrazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydro-isoquinoline

Step A:4-(4-Chlorophenyl)-1,1-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolinewas prepared following similar methods described in Step A to Step E ofExample 9 starting from 2-(3-bromophenyl)propan-2-amine and2-bromo-1-(4-chlorophenyl)ethanone. 3-Trifluoromethyl-6-chloropyridazine(95 mg, 0.52 mmol) was added to a mixture of the aforementioned boronateester (285 mg, 0.43 mmol) and cesium carbonate (423 mg, 1.30 mmol) inDMF (5 mL) and water (0.65 mL). The reaction mixture was degassed withargon. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (35 mg, 0.043 mmol) was added and the reactionmixture was stirred at 90° C. for 1.5 hours, cooled, diluted with water,and extracted with ethyl acetate (3×). The combined organic extractswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated. Purification by flash column chromatography [3% methanol(containing 10% concentrated ammonium hydroxide)/dichloromethane] gave4-(4-chlorophenyl)-1,1-dimethyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(140 mg, 78% over 2 steps): ¹H NMR (CDCl₃, 300 MHz) ¹H NMR (CDCl₃, 500MHz) δ 8.23 (d, J=1.7 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.87 (d, J=8.9Hz, 1H), 7.73 (dd, J=8.1, 1.8 Hz, 1H), 7.31-7.26 (m, 2H), 7.07-7.02 (m,3H), 4.13 (t, J=5.3 Hz, 1H), 3.45 (dd, J=13.5, 5.0 Hz, 1H), 3.12 (dd,J=13.5, 5.8 Hz, 1H), 1.62 (s, 3H), 1.58 (s, 3H); ESI MS m/z 418 [M+H]⁺.

Step B: The racemic4-(4-chlorophenyl)-1,1-dimethyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline(153 mg) from Step A was resolved by preparative chiral HPLC (ChiralPakAD column, using 80:20:0.1 heptane/isopropanol/diethylamine as theeluent) to give the (−)-enantiomer ([α]²⁵ _(D) −41.4° (c 0.22,methanol)) and the (+)-enantiomer ([α]²⁵ _(D) +41.4° (c 0.21,methanol)).

Example 36 Preparation of7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline,L-Tartrate Salt

Step A: To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) inmethanol (1 L) was added a 40% aqueous solution of methylamine (113 ml,1.31 mol) followed by 1 hour stirring at 0° C. Sodium borohydride (75 g,1.98 mol) was added portionwise at 0° C. and the reaction mixture wasstirred for 1 hour. The solution was concentrated to a smaller volumethen, was diluted with water (200 mL) and the resulting solution wasextracted with methylene chloride (3×500 mL). The combined organicextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to afford the crude N-methylbenzylamine (220 g,quantitative) as clear oil, which was used in the next step withoutfurther purification: ¹H NMR (CDCl₃, 500 MHz) δ.7.23 (t, J=8.0 Hz, 1H),6.92-6.88 (m, 2H), 6.81-6.78 (m, 1H), 3.80 (s, 3H), 3.73 (s, 2H), 2.45(s, 3H), 2.07 (broad s, 1H).

Step B: To a solution of the above amine (6.2 g, 41.00 mmol) from Step Ain methylene chloride (100 mL) was added 3,4-dichlorophenacyl bromide(10.0 g, 37.3 mmol) and the resulting mixture was stirred at 0° C. for 1hour prior to the addition of triethylamine (5.20 mL, 37.31 mmol),followed by 1 hour stirring at 0° C. The reaction mixture was dilutedwith water (100 mL) then the aqueous phase was extracted with additionalmethylene chloride (3×75 mL). The combined extracts were dried oversodium sulfate, filtered, and concentrated to afford1-(3,4-dichlorophenyl)-2-(3-methoxybenzyl)(methyl)amino)ethanone (15.08g) as a light yellow oil, which was used in the next step withoutfurther purification: ¹H NMR (500 MHz, CDCl₃) δ 8.08 (d, J=2.0 Hz, 1H),7.78 (dd, J=8.5; 2.0 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz,1H), 6.90 (d, J=7.5 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.82 (dd, J=8.0;2.5 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 2H), 3.60 (s, 2H), 2.33 (s, 3H).

Step C: To a solution of the ketone (˜37 mmol) from Step B in methanol(150 mL), was added sodium borohydride (2.11 g, 55.79 mmol) portionwiseat 0° C. The reaction mixture was first stirred for 2 hours then, wasdiluted with water (100 mL) and extracted with methylene chloride (3×300mL). The combined organic extracts were dried over sodium sulfate,filtered, and concentrated to dryness under reduced pressure to affordthe crude alcohol (14.14 g) as a yellow oil, which was used withoutfurther purification in the next step: ¹H NMR (500 MHz, CDCl₃) δ 7.45(d, J=2.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.16 (dd,J=8.0; 2.0 Hz, 1H), 6.90-6.81 (m, 3H), 4.70-4.65 (m, 1H), 3.81 (s, 3H),3.70 (d, J=13.0 Hz, 1H), 3.50 (d, J=13.0 Hz, 1H), 2.54-2.49 (m, 2H),2.32 (s, 3H).

Step D: To a solution of the alcohol (˜37 mmol) from Step C in methylenechloride (200 mL) was added concentrated sulfuric acid (12 mL, 235 mol)and the mixture was stirred at 0° C. for 28 hours. The reaction wasquenched by adding a 6N NaOH solution till pH˜9. The aqueous phase wasextracted with additional methylene chloride (3×). The combined organicextracts were washed with brine (3×), dried over sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (1:1:1: to 1:1:2 dichloromethane/hexanes/ethyl acetate)to afford4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(7.0 g, 59% over 3 steps) as a light yellow oil: ¹H NMR (500 MHz, CDCl₃)δ 7.33 (d, J=8.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.5; 2.0Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 6.66 (dd, J=8.5; 3.0 hz, 1H), 6.61 (d,J=2.5 Hz, 1H), 4.16-4.11 (m, 1H), 3.77 (s, 3H), 3.67-3.59 (m, 2H), 2.92(dd, J=11.5; 5.5 Hz, 1H), 2.55 (dd, J=11.5; 7.0 Hz, 1H), 2.39 (s, 3H).The undesired 5-methoxy isomer was also isolated (1.20 g, 10% over 3steps).

Step E: The racemic4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(7.0 g) from Step D above was resolved by preparative chiral HPLC(CHIRALPAK AD column, using 80:20:0.1 heptane/2-propanol/diethylamine asthe eluent) to give the (+)-enantiomer ([α]²⁵ _(D) +31.9° (c 0.49,methanol)) (3.68 g) as a colorless oil and the (−)-enantiomer (3.99 g)as a colorless oil.

Step F: A solution of(+)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(3.68 g, 11.42 mmol) in a mixture of acetic acid (20 mL) and 48% aqueoushydrobromic acid solution (50 mL) was refluxed for 8 hours. The ice-coldreaction mixture was basified with a concentrated aqueous solution ofsodium hydroxide and a saturated aqueous solution of sodium bicarbonateuntil reaching a pH of about 8-9 and was extracted with dichloromethane(3×). The combined extracts were dried over sodium sulfate, filtered,and concentrated in vacuo to afford the crude alcohol (2.6 g) as ayellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.32 (d, J=8.5 Hz, 1H), 7.26 (d,J=2.0 Hz, 1H), 7.01 (dd, J=8.0; 2.0 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H),6.54 (d, J=8.5 Hz, 1H), 6.49 (broad s, 1H), 4.15-4.10 (m, 1H), 3.60 (d,J=15.0 Hz, 1H), 3.56 (d, J=15.0 Hz, 1H), 2.96 (dd, J=11.5; 5.7 Hz, 1H),2.52 (dd, J=11.5, 8.0 Hz, 1H), 2.39 (s, 3H).

Step G: To a solution of the phenol from Step F above (2.1 g, 6.81 mmol)and pyridine (0.72 mL, 8.85 mmol) in dichloromethane (60 mL) was addedtrifluoromethanesulfonic anhydride (1.37 mL, 8.14 mmol) at −78° C. Thereaction was allowed to warm to 0° C. and stirred for 1 hour. Thereaction mixture was diluted with water (20 mL) and extracted withdichloromethane (3×). The combined extracts were dried over sodiumsulfate, filtered, and concentrated to give the crude triflate as ayellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J=8.5 Hz, 1H), 7.30 (d,J=2.0 Hz, 1H), 7.03-6.98 (m, 3H), 6.94 (d, J=8.5 Hz, 1H), 4.19-4.15 (m,1H), 3.68 (s, 2H), 2.96 (dd, J=11.7; 5.5 Hz, 1H), 2.60 (dd, J=11.7, 7.5Hz, 1H), 2.42 (s, 3H).

Step H: A mixture of the triflate from Step G above (˜6.8 mmol),bis(pinacolato)diboron (2.07 g, 8.15 mmol), and potassium acetate (2.05g, 20.8 mmol) in dimethyl sulfoxide (35 mL) was degassed with argon. Tothis mixture was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.40 g,0.55 mmol). The resulting mixture was degassed with argon and thenheated at 85° C. for 2 hours. The cold reaction mixture was diluted withethyl acetate (150 mL). The resulting solution was washed with water(2×40 mL), brine (1×40 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. A Purification flash chromatography column(eluent, 1:1:1 to 1:1:2 dichloromethane/hexanes/ethyl acetate) gave thedesired boronate ester (2.6 g, 91% over 2 steps) as a yellow solid. ¹HNMR (500 MHz, CDCl₃) δ 7.55 (s, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.33 (d,J=8.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H),6.85 (d, J=8.0 Hz, 1H), 4.23 (t, J=6.5 Hz, 1H), 3.71 (d, J=15.0 Hz, 1H),3.67 (d, J=15.0 Hz, 1H), 2.98 (dd, J=11.4, 5.3 Hz, 1H), 2.56 (dd,J=11.4, 7.5 Hz, 1H), 2.41 (s, 3H), 1.33 (s, 12H).

Step I: To a solution of the boronate ester (2.6 g, 6.22 mmol) from StepF and proton sponge (2.6 g, 12.1 mmol) in dichloroethane (80 mL) at 0°C. was added 1-chloroethyl chloroformate (2.4 mL, 22.1 mmol). Themixture was stirred at 0° C. for 15 minutes, then was refluxed for 40minutes and was concentrated in vacuo. The residue was filtered througha short pad of silica gel (eluent, 1:1:1 dichloromethane/hexanes/ethylacetate) and the filtrate was concentrated in vacuo. The residue wasdiluted with methanol (160 mL), heated to reflux for 1 hour andconcentrated in vacuo to give the4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolineas a brown foam.

Step J: A solution of the product from Step I (˜6.2 mmol), (Boc)₂O (3.60g, 16.4 mmol), triethylamine (1.5 mL, 10.7 mmol) and DMAP (0.26 g, 2.20mmol) in dichloromethane (120 mL) was stirred at room temperature for 4hours. The reaction was quenched by the addition of water (50 mL) then,the aqueous phase was extracted with additional dichloromethane (2×100mL). The combined extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo. A purification by flash column chromatography(eluent, 47.5:47.5:5 to 1:1:1 dichloromethane/hexanes/ethyl acetate)gave the boc-protected tetrahydroisoquinoline (1.82 g, 58% over 3 steps)as a white foam. ¹H NMR (500 MHz, CDCl₃) δ 7.65 (s, 1H), 7.58 (d, J=7.5Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.95 (d, J=7.0 Hz, 1H),6.97-6.93 and 6.83-6.78 (m, 1H), 5.01-4.95 and 4.48-4.43 (m, 1H),4.56-4.52 (m, 1H), 3.95 (s, 1H), 3.83-3.44 (m, 2H), 1.43 and 1.26 (2s,9H), 1.33 (s, 12H).

Step K: A dry flask was loaded with the boronate ester (0.8 g, 1.59mmol) from Step J, 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (0.35 g, 1.78mmol), cesium carbonate (0.97 g, 2.98 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (87 mg, 0.12 mmol). The flask was blanketed withargon then, DMF (20 mL) and water (4 mL) were added followed by a shortsonication. The reaction mixture was heated to 80° C. for 1 hour. Thecold reaction mixture was diluted with water (20 mL) and the aqueouslayer was extracted with dichloromethane (3×60 mL). The combined organicphases were concentrated in vacuo. Purification by flash columnchromatography (eluent, 1:1:1 to 1:1:2 dichloromethane/hexanes/ethylacetate) gave the Boc-protected7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline(0.86 g, quantitative) as a white foam.

Step L: A solution of the Boc-protected7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline(0.85 g, 1.72 mmol) and concentrated hydrochloric acid (4.0 mL) inethanol (10 mL) was stirred at room temperature for 1 hour. The reactionmixture was concentrated to dryness in vacuo. The residue was dissolvedin a mixture of dichloromethane (14 mL) and TFA (10 mL), stirred at roomtemperature for 1 hour then concentrated in vacuo. The syrup thusobtained was diluted with dichloromethane and treated with a saturatedaqueous solution of sodium bicarbonate until pH 8-9. The aqueous phasewas extracted with additional dichloromethane (3×) and the organicphases were dried over sodium sulfate, filtered, and concentrated invacuo to give7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline(0.59 g, 87%) as a white foam.

Step M: To a solution of the product (0.59 g, 1.49 mmol) from Step B inethanol was added L-tartaric acid (0.22 g, 1.49 mmol). The slurry wasfiltered. The cake was rinsed with ethanol and dried to give7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline,L-tartrate salt (0.49 g, 59%, AUC HPLC>99%) as a white solid. [[α]²⁵_(D) +9.0° (c 0.11, methanol)]. ¹H NMR (500 MHz, CD₃OD) δ 9.09 (s, 1H),8.53 (s, 1H), 8.02 (dd, J=9.0, 2.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.68(s, 1H), 7.64-7.61 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.48 (d, J=2.0 Hz,1H), 7.24 (dd, J=8.0, 2.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.65-4.57 (m,2H), 4.52 (d, J=16.0 Hz, 1H), 4.41 (s, 2H), 3.79 (dd, J=12.5, 6.0 Hz,1H), 3.44 (t, J=12.5 Hz, 1H). ESI MS m/z 395 [M+H]⁺. Anal. Calcd. forC₂₁H₁₆Cl₂N₄.C₄H₆O₆.0.5H₂O: C, 54.16; H, 4.18; N, 10.11.

Found: C, 54.07; H, 3.92; N, 9.97.

The L-tartrate of the(−)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinewas prepared using(−)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinefollowing similar steps described for the synthesis of the(+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline,L-tartrate salt ([α]²⁴ _(D) −6.0° (c 0.10, methanol)).

Example 37 Alternate Synthesis of Example 36

Step A: To a solution of the triflate (9.5 g, 21.6 mmol) from step G inExample 36 and bis(pinacolato)diboron (6.6 g, 25.9 mmol) in dimethylsulfoxide (200 mL) was added potassium acetate (6.4 g, 64.8 mmol). Thesolution was degassed with argon for 5 minutes and thendichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (1.6 g, 2.2mmol) was added to it. The reaction mixture was degassed with argon for5 minutes, heated at 80° C. for 1 hour, and then cooled to roomtemperature. To this solution were added6-bromo-[1,2,4]triazolo[1,5-α]pyridine (4.8 g, 23.8 mmol) and an aqueoussolution of cesium carbonate (21.1 g, 64.8 mmol in 87 mL of water). Theresultant solution was degassed with argon and thendichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.8 g, 1.1mmol) was added to it. The reaction mixture was degassed with argon andheated at 80° C. for 1 hour. A dark sticky oil formed during thereaction. The dark supernatant solution was poured out, diluted withwater, and extracted with ethyl acetate (3×), which was dried oversodium sulfate and concentrated in vacuo. The oil left was dissolved indichloromethane and the resultant solution was washed with water, driedover sodium sulfate, and concentrated in vacuo. The combined crudeproduct was purified by flash column chromatography (100% ethyl acetateto 92:7.2:0.8 ethyl acetate/methanol/ammonium hydroxide) to give7-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline(7.7 g, 87%, AUC HPLC 97.6%) as a brown foam: ¹H NMR (500 MHz, CDCl₃) δ8.77 (s, 1H), 8.37 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.76 (d, J=9.0 Hz,1H), 7.39-7.32 (m, 4H), 7.09 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H),4.26 (t, J=6.5 Hz, 1H), 3.75 (app s, 2H), 3.01 (dd, J=11.5, 5.5 Hz, 1H),2.64 (dd, J=11.5, 6.5 Hz, 1H), 2.46 (s, 3H).

Step B: To a solution of the7-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline(7.2 g, 17.6 mmol) from step A above in 1,2-dichloroethane (180 mL) at0° C. was added proton sponge (3.8 g, 17.6 mmol), followed by additionof 1-chloroethyl chloroformate (2.3 mL, 21.1 mmol). After the addition,the reaction solution was stirred at 0° C. for 20 minutes and roomtemperature for 14 hours. Additional 1-chloroethyl chloroformate (0.5mL, 4.6 mmol) was added to the reaction solution. The reaction solutionwas stirred for another 3 hours and then it was cooled to 0° C., washedwith aqueous hydrochloric acid (1N). Precipitate formed during the acidwash. The organic extract was separated, dried over sodium sulfate, andconcentrated in vacuo. The residue obtained was purified by flash columnchromatography (dichloromethane to 95:4.5:0.5dichloromethane/methanol/ammonium hydroxide) to give two batches ofpartially purified carbamate intermediates, which were dissolved inmethanol and refluxed for 1 hour. The reaction solutions wereconcentrated in vacuo and the crude product obtained was purified by acombination of flash column chromatography (ethyl acetate to 88:10.2:0.8ethyl acetate/methanol/ammonium hydroxide) and preparative thin layerchromatography (ethyl acetate/methanol/ammonium hydroxide 90:9:1) togive the desired des-methyl tetrahydroisoquinoline (3.8 g, 54%; AUC HPLC98.7%) as a light pink foam: ¹H NMR (500 MHz, CDCl₃) δ 8.78-8.77 (m,1H), 8.37 (s, 1H), 7.83 (dd, J=9.5, 1.0 Hz, 1H), 7.77 (dd, J=9.0, 1.5Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.36-7.26 (m, 3H), 7.05-7.00 (m, 2H),4.24 (d, J=16.5 Hz, 1H), 4.17 (d, J=16.5 Hz, 1H), 4.13-4.11 (m, 1H),3.44 (dd, J=12.5, 5.0 Hz, 1H), 3.11 (dd, J=13.0, 6.0 Hz, 1H).

Step C: To a solution of des-methyl tetrahydroisoquinoline (3.75 g, 9.48mmol) from step B above in ethanol (80 mL) was added activated carbon(3.0 g) and stirred at room temperature for 30 minutes. The carbon wasremoved by filtration and the filtrate obtained was concentrated invacuo. The resultant oil was dissolved in ethanol (60 mL) and a solutionof L-tartaric acid (1.44 g, 9.5 mmol) in ethanol (20 mL) was added. Uponwhich, white precipitate formed immediately. The slurry was stirred atroom temperature for 10 minutes and filtered. The cake obtained wasstirred in hot ethanol (70° C.) for 3 hours and filtered. The cakeobtained was dried in vacuo at 50-60° C. for 40 hours to give the(+)-7-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolineL-tartrate (3.7 g, 73%; AUC HPLC 99.4% at 250 nm) as an off-white solid[α]²³ _(D) +16.8° (c 0.13, methanol): ¹H NMR (500 MHz, CD₃OD) δ 9.09 (s,1H), 8.53 (s, 1H), 8.02 (dd, J=9.0; 2.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H),7.68 (s, 1H), 7.64-7.61 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.48 (d, J=2.0Hz, 1H), 7.24 (dd, J=8.0; 2.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.65-4.57(m, 2H), 4.52 (d, J=16.0 Hz, 1H), 4.41 (s, 2H), 3.79 (dd, J=12.5; 6.0Hz, 1H), 3.44 (t, J=12.5 Hz. 1H). ESI MS m/z 395 [M+H]⁺ Anal. Calcd. forC₂₁H₁₆Cl₂N₄.C₄H₆O₆.0.5H₂O: C, 54.16; H, 4.18; N, 10.11. Found: C, 53.96;H, 3.98; N, 9.94.

Example 38 Alternative Synthesis of Example 36 (Hydrochloride)

Step A: To a 1 L round-bottom flask was added 2-amino-5-bromopyridine(100 g, 578 mmol), DMF-DMA (101 mL, 751 mmol) and 2-propanol (200 mL).The mixture was heated to reflux for 3 h to give a clear dark solution.It was then cooled to 50° C. and hydroxylamine hydrochloride (52.2 g,751 mmol) was added. The mixture was stirred at 50° C. overnight to givea yellow suspension. The precipitate was collected by filtration. Theblack filtrate was concentrated and the residue was stirred in EtOH (20mL) for 20 min. The solid was collected by filtration. The combinedsolids were dried in an oven to giveN-(5-bromopyridin-2-yl)-N′-hydroxyformimidamide as a sandy solid (94 g,75% yield).

Step B: N-(5-bromopyridin-2-yl)-N′-hydroxyformimidamide was dissolved inTHF (1 L). To the solution at 10° C. was added trifluoroacetic anhydride(106 mL, 751 mmol) slowly to control the reaction temperature below 20°C. After the addition was complete, the mixture was warmed to roomtemperature and stirred for 2 h. After the reaction was finished, it wasquenched with Na₂CO₃ aqueous solution to adjust pH>7. The organicsolvent was removed under reduced pressure, and the product was thenextracted with DCM (4×300 mL). The combined organic layers were driedover Na₂SO₄ and concentrated to dryness. The residue was stirred inethyl ether (100 mL) and the product6-bromo-[1,2,4]triazolo[1,5-a]pyridine was collected by filtration as anoff-white solid (50 g, 58% yield).

Step C: To a mixture of 3-formylphenylboronic acid (21.41 g, 143 mmol),6-bromo-[1,2,4]triazolo[1,5-a]pyridine (28.27 g, 143 mmol) in DMSO (600mL) and water (50 mL) was added Pd(dppf)Cl₂ (5.83 g, 7.14 mmol) andCs₂CO₃ (116 g, 357 mmol). The reaction temperature reached 45° C. afterthe addition. HPLC showed that starting materials were consumed after 15min. The reaction was diluted with water (400 mL). The black precipitatewas collected by filtration and dissolved in DCM (300 mL), and washedwith brine (200 mL). The aqueous layer was back extracted with DCM (100mL). The combined organic layers were filtered through a Celite pad andthe filtrate was concentrated to give a black solid mixture. The productwas recrystallized in methanol to give3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde (27.4 g, 123 mmol,86% yield) as a pale grey solid: m/z=224.0 [M+1]; ¹H NMR (400 MHz,DMSO-D6) δ ppm 7.74 (t, J=7.68 Hz, 1H), 7.91-8.02 (m, 2H), 8.11 (dd,J=9.19, 1.89 Hz, 1H), 8.17 (d, J=7.81 Hz, 1H), 8.36 (s, 1H), 8.57 (s,1H), 9.45 (s, 1H), 10.11 (s, 1H).

Step D: A mixture of α-bromo-3,4′-dichloroacetophenone (26.7 g, 100mmol), hexamethylenetetramine (HMTA) (13.97 g, 100 mmol) and NaI (0.5 g)was stirred at room temperature overnight. HPLC analysis indicatedconsumption of starting materials. The ammonium intermediate wascollected by filtration as a white solid, washed with acetone and dried(36 g, 89% yield).

To a solution of the intermediate (36 g, 88 mmol) in EtOH (500 mL) wasadded 12 N HCl (75 mL, 0.9 mol). The mixture was stirred at 76° C.overnight, and then cooled to room temperature. The product2-amino-1-(3,4-dichlorophenyl)ethanone hydrochloride was obtained as acrystal solid by filtration (20.2 g, 95% yield): ¹H NMR (400 MHz,DMSO-D6) δ ppm 4.62 (s, 2H), 7.79-7.94 (m, 1H), 7.98 (dd, J=8.56, 2.01Hz, 1H), 8.26 (d, J=2.01 Hz, 1H), 8.48 (s, 3H).

Step E: To a solution of 2-amino-1-(3,4-dichlorophenyl)ethanonehydrochloride (50 g, 208 mmol) in MeOH (200 mL) was added sodiumborohydride (7.86 g, 208 mmol) at 0° C. slowly. HPLC indicated 100%conversion after 10 min. A solution of3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde (46.4 g, 208 mmol) inDCM/MeOH (180 mL/50 mL) was added to the previous solution in oneportion at room temperature. The mixed solution was stirred at RT for 2h, then sodium borohydride (7.86 g, 208 mmol) was added. HPLC indicated100% conversion after 10 min. Most of the solvent was removed and theresidual was dissolved in DCM/NH₄OH (4N) (1 L/1 L). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated to ˜250 mL.The product2-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzylamino)-1-(3,4-dichlorophenyl)ethanolin DCM solution was used in the next step without further purification(HPLC area 92%): m/z=413.1 [M+1]; ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm2.72 (dd, J=12.21, 8.69 Hz, 1H), 2.96 (dd, J=12.34, 3.53 Hz, 1H),3.85-3.98 (m, 2H), 4.69 (dd, J=8.56, 3.53 Hz, 1H), 7.18 (dd, J=8.31,1.76 Hz, 1H), 7.34-7.42 (m, 2H), 7.43-7.56 (m, 4H), 7.72-7.88 (m, 2H),8.36 (s, 1H), 8.78 (s, 1H).

Step F: A solution of concentrated sulfuric acid (500 g, 5.0 mol) in a 3L round bottom flask was cooled to 0° C. with an ice bath. To the flaskwas added dropwise a solution of2-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzylamino)-1-(3,4-dichlorophenyl)ethanol(79 g, 0.191 mol) in DCM (250 mL). The addition was finished in 30 minand the reaction temperature was controlled in the range of 10-20° C.DCM was blown away with nitrogen gas during the addition. Theevaporation of DCM helped to lower the reaction temperature. The mixturesolution was stirred at RT overnight. HPLC indicated no remainingstarting material. The HPLC area ratio of7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolineand5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinewas 75:25. The reaction mixture was cooled to 0° C. Isopropanol (2 L)was added to the solution slowly, maintaining temperature<0° C. Thesolid (desired isomer 92% purity) was obtained by filtration. The solidwas then dissolved in AcOEt (1 L) and the pH adjusted to 10 with NH₄OH.The water layer was extracted with EtOAc twice. The combined organiclayers were washed with water, dried over Na₂SO₄ and concentrated. Theresidue was dissolved in EtOH (250 mL) and then 1.1 eq ofmethanesulfonic acid (20.20 g, 0.21 mol) was added and the solutionstirred overnight. The resulting precipitate methanesulfonic acid salt(98% purity) was filtered. This was dissolved in water and the pHadjusted with NH₄OH to 10, then extracted with AcOEt twice. The combinedextracts were washed with water and dried over Na₂SO₄. After removal ofsolvent,7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinewas obtained in an amorphous state (40.8 g, 54% yield): m/z=395.0 [M+1];¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.05 (dd, J=12.00, 8.00 Hz, 1H),3.40 (dd, J=12.00, 4.00 Hz, 1H), 4.05-4.25 (m, 3H), 6.96 (m, 2H),7.25-7.35 (m, 4H), 7.70-7.80 (m, 2H), 8.32 (s, 1H), 8.74 (s, 1H).

Step G: To a solution of7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline(25.2 g, 63.8 mmol) in DMF (30 ml) was added di-tert-butyl dicarbonate(13.91 g, 63.8 mmol). The reaction mixture was stirred at RT for 1 h,then AcOEt (500 ml) was added. The solution was washed with brine andwater. The organic layer was dried over Na₂SO₄. After removal ofsolvent, solid rac-tert-butyl7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(30.6 g, 61.8 mmol, 97% yield) was obtained by recrystallization fromMeOH; m/z=495.1 [M+1]; ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.30 (s,9H), 3.60-4.15 (m, 3H), 4.40-5.10 (m, 2H), 6.84-7.05 (m, 2H), 7.13 (d,J=1.51 Hz, 1H), 7.35 (m, 3H), 7.78 (dd, J=8.31, 1.77 Hz, 2H), 8.31 (s,1H), 8.72 (s, 1H).

Step H: Chiral SFC separation on a Chiralpak AS-H column (3×25 cm, 5 μm;eluent: CO2/(MeOH/TEA=100/0.2(v/v))=75/25; 220 nm) yielded(+)-tert-butyl7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(99.7% ee).

Step I: To a solution of the (+)-enantiomer from Step H (32.41 g, 65.43mmol) in DCM (150 ml) was added hydrogen chloride-EtOH solution (2.5N,250 mL) and EtOH 500 mL. The reaction mixture was stirred at 70° C. for2 h. After removal of the solvent, the residue was refluxed in 1000 mlAcOEt for 1 h. The product(+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride (27.4 g, 97% yield) was obtained after filtration anddrying. m/z=395.1 [M+1]; ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.70 (m, 2H),4.40-4.65 (m, 3H), 6.90 (d, 7.80 Hz, 1H), 7.35 (dd, J=7.8, 2 Hz, 1H),7.68 (m, 4H), 8.58 (s, 1H), 9.38 (s, 1H), 9.8 (bs, 2H).

Example 39 Preparation of (+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline,L-tartrate Salt

Step A: To a solution of1-(4-fluoro-3-methoxyphenyl)-N-methylmethanamine (0.9 g, 5.39 mmol) inethanol (8.0 mL) was added potassium carbonate (0.6 g, 4.48 mmol) and2-bromo-1-(3,4-dichlorophenyl)ethanone (1.2 g, 4.48 mmol). The reactionsolution was stirred for 2.5 hours at room temperature and then sodiumborohydride (0.2 g, 5.83 mmol) was added to it portionwise at 0° C. Thereaction mixture was stirred overnight while warming up to roomtemperature. The reaction solution was concentrated in vacuo. The slurryobtained was quenched with water and extracted with methylene chloride.The combined organic extracts were washed with brine (2×200 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by flash column chromatography (1:1 to1:9 hexanes/ethyl acetate) to afford1-(3,4-dichlorophenyl)-2-(4-fluoro-3-methoxybenzyl)(methyl)amino)ethanol(1.9 g): ¹H NMR (CDCl₃, 300 MHz) δ 7.45 (d, J=1.5 Hz, 1H), 7.39 (d,J=3.0 Hz, 1H), 7.16 (dd, J=8.0, 2.0 Hz, 1H), 7.05-7.01 (m, 1H), 6.91(dd, J=8.0, 2.0 Hz, 1H), 6.81-6.78 (m, 1H), 4.69 (t, J=7.0 Hz, 1H), 3.98(br.s, 1H), 3.90 (s, 3H), 3.67 (d, J=13.5 Hz, 1H), 3.47 (d, J=13.0 Hz,1H), 2.50 (d, J=7.0 Hz, 2H), 2.32 (s, 3H); ESI MS m/z 358 [M+H]⁺.

Step B: To a solution of the alcohol (1.1 g, 2.93 mmol) from Step Aabove in methylene chloride (10.0 mL) was added concentrated sulfuricacid (1.5 mL, 0.56 mmol). The reaction mixture was stirred at 0° C. for30 minutes and at room temperature for 2 hours. The reaction solutionwas quenched at 0° C. by addition of an aqueous solution of sodiumhydroxide (2N) and the aqueous phase was extracted with additionalmethylene chloride (3×). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography (7:3 to 1:9 hexanes/ethylacetate) to afford4-(3,4-dichlorophenyl)-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(1.0 g, 98%): ¹H NMR (500 MHz, CDCl₃) δ 7.35 (d, J=8.0 Hz, 1H), 7.28 (d,J=2.5 Hz, 1H), 7.03 (dd, J=8.0, 2.0 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H),6.55 (d, J=12.0 Hz, 1H), 4.09 (t, J=7.5 Hz, 1H), 3.87 (s, 3H), 3.60 (s,2H), 2.92 (dd, J=12.0, 5.5 Hz, 1H), 2.53 (dd, J=11.5, 7.5 Hz, 1H), 2.41(s, 3H); ESI MS m/z 340 [M+H]⁺.

Step C: The racemic 7-methoxy tetrahydroisoquinole from Step B above(8.5 g) was resolved by preparative chiral HPLC (CHIRALPAK AD column,using 80:20:0.1 heptane/isopropanol/diethylamine as the eluent) to give(+) enantiomer (4.0 g) and (−) enantiomer (4.0 g).

Step D: To a solution of (+) 7-methoxytetrahydroisoquinoline from Step Cabove (3.4 g, 11.70 mmol) in hydrobromic acid (90 mL, 48% solution inwater) was added acetic acid (48 mL). The reaction solution was stirredat 110° C. overnight under nitrogen and then concentrated under reducedpressure. The resultant solution was quenched with sodium bicarbonateand extracted with dichloromethane, dried over aqueous sodium sulfate,and concentrated under reduced pressure to give the desired phenol (3.6g, crude), which was used in the next step without further purification:¹H NMR (MeOD, 500 MHz) δ 7.44 (d, J=7.0 Hz, 1H), 7.33 (d, J=1.5 Hz, 1H),7.11 (dd, J=8.0, 2.0 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.46 (d, J=12.0Hz, 1H), 4.19 (t, J=7.0 Hz, 1H), 3.67-3.53 (m, 2H), 3.01 (dd, J=11.5,5.5 Hz, 1H), 2.52 (dd, J=12.0, 9.0 Hz, 1H), 2.40 (s, 3H); ESI MS m/z 326[M+H]⁺.

Step E: To a solution of the phenol (2.5 g, 7.79 mmol) from Step D abovein dichloromethane (30 mL) at 0° C. was added pyridine (0.8 mL, 10.12mmol) followed by slow addition of trifluoromethanesulfonic anhydride(1.4 mL, 8.18 mmol) dropwise. The resultant reaction solution wasstirred at 0° C. for 1 hour, and then was quenched with aqueoussaturated sodium bicarbonate. The organic extract was separated and theaqueous layer was extracted with dichloromethane (3×). The combinedorganic extract was washed with 1:1 water/brine, dried over sodiumsulfate, and concentrated under reduced pressure to give the desiredtriflate (3.5 g) as a yellow oil: ¹H NMR (CDCl₃, 500 MHz) δ 7.39 (dd,J=8.0, 2.5 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.02(dd, J=6.0, 2.0 Hz, 1H), 6.75 (d, J=10.0 Hz, 1H), 4.14 (t, J=6.5 Hz,1H), 3.61 (s, 2H), 2.95 (dd, J=11.5, 5.5 Hz, 1H), 2.58 (dd, J=11.5, 7.0Hz, 1H), 2.43 (s, 3H).

Step F: To a mixture of triflate (3.5 g, 7.57 mmol) in Step E abovebis(pinacolato)diboron (2.3 g, 9.09 mmol) and potassium acetate (2.2 g,22.72 mmol) were added in DMSO (100.0 mL). The reaction solution waspurged with argon for 10 minutes, and then1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (0.5 g, 0.61 mmol)was added to it. The reaction solution was degassed again with argon for5 minutes and heated at 80° C. overnight. The reaction solution was thencooled to room temperature, diluted with ethyl acetate, washed withsaturated aqueous sodium bicarbonate, dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained waspurified by flash column chromatography (90:9:1dichloromethane/methanol/concentrated ammonia) to give4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline(0.1 g, 3%): ¹H NMR (CDCl₃, 500 MHz) δ 7.48 (d, J=6.0 Hz, 1H), 7.37-7.34(m, 1H), 7.27 (s, 1H), 7.00 (dd, J=8.0, 2.0 Hz, 1H), 6.56-6.51 (m, 1H),4.19 (t, J=6.5 Hz, 1H), 3.69-3.53 (m, 2H), 2.96 (dd, J=11.5, 5.5 Hz,1H), 2.53 (dd, J=11.5, 7.5 Hz, 1H), 2.40 (s, 3H), 1.35 (s, 12H).

Step G: A mixture of the boronate ester from Step F (350 mg, 0.80 mmol,prepared in Step F), 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (191 mg,0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL)and N,N-dimethylformamide (4 mL) was degassed with argon and then[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethaneadduct (33 mg, 0.040 mmol) was added. The mixture was degassed again andthen heated to 90° C. for 2.5 hours. The reaction mixture was dilutedwith ethyl acetate (30 mL), washed with water (2×), brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspartially purified by column chromatography (methylene chloride to90:9:1 methylene chloride/methanol/ammonium hydroxide) to give(+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolinewas obtained in 54% yield as a brown oil: ESI MS m/z 428 [M+H]⁺.

Step H: To(+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline(160 mg, 0.37 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine(160 mg, 0.37 mmol) in 1,2-dichloroethane (5 mL) was added 1-chlorethylchloroformate (0.082 mL, 0.75 mmol) dropwise. The mixture was heated toreflux for 3 hours and then cooled to ambient temperature. The reactionmixture was diluted with methylene chloride and washed with 1N HCl,water, dried over sodium sulfate, filtered, and concentrated in vacuo.To the residue was added methanol (15 mL) and the mixture was heated toreflux. After 1 h, the reaction mixture was cooled to ambienttemperature and concentrated under reduced pressure. The residue wastaken up in ethyl acetate (30 mL) and washed with saturated aqueoussodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography (methylene chloride to 90:9:1methylene chloride/methanol/ammonium hydroxide) and preparative TLC(90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtainedmaterial (10 mg, 0.024 mmol) in acetonitrile (1.5 mL) was addedL-tartaric acid (3.6 mg, 0.024 mmol) in water (2 mL). The resultantsolution was lyophilized to give(+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline,L-tartrate salt (19 mg, 9%, AUC HPLC>99%) as a white powder: ¹H NMR(CD₃OD, 500 MHz) 9.03 (s, 1H), 8.47 (s, 1H), 7.93 (d, J=9.0 Hz, 1H),7.87 (d, J=9.5 Hz, 1H), 7.60-7.56 (m, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.24(dd, J=8.0, 1.5 Hz, 1H), 6.80 (d, J=11.5 Hz, 1H), 4.56-4.46 (m, 3H),4.43 (s, 2.3H), 3.78-3.73 (m, 1H), 3.41-3.38 (m, 1H); ESI MS m/z 413[M+H]⁺; [ ]24D+21.2° (c 0.11, methanol).

Example 40 Preparation of4-(3,4-dichlorophenyl)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

Step A: Cerium(III) chloride heptahydrate (29.8 g, 80 mmol) was driedwith magnetic stirring at 145° C. under vacuum overnight.Tetrahydrofuran (160 mL) was added and the white suspension was stirredat room temperature for 2 hours and then cooled with dry-ice/acetonebath. To this dry-ice/acetone bath cooled solution was added methyllithium (1.6 M in ether, 50 mL, 80 mmol). The reaction mixture wasstirred for 30 minutes and then a solution of 3-bromobenzonitrile (3.68g, 20 mmol) in tetrahydrofuran (10 mL) was added. The resulting reactionmixture was stirred at −70 to −60° C. for 5 hours. Concentrated ammoniumhydroxide (50 mL) was added at −40° C. The mixture was allowed to warmto room temperature and filtered through Celite. The Celite bed waswashed with dichloromethane. The filtrate was extracted withdichloromethane (3×). The combined extracts were washed with brine,dried over sodium sulfate, and concentrated under reduced pressure togive 1,1-dimethyl-3′-bromobenzyl amine (4.33 g, >99% crude) as a clearoil, which was used in the next step without further purification: ESIMS m/z 214 [M+H]⁺.

Step B: To a solution of 2-bromo-1-(3,4-dichlorophenyl)ethanone (5.1 g,18.96 mmol) in methanol (50 mL) at 0° C. was added sodium borohydride(2.1 g, 56.98 mmol). The reaction mixture was stirred at 0° C. for 1hour. The pH was adjusted to 12 using 2 M sodium hydroxide solution, thesolvent was then removed under reduced pressure and the residue wasdissolved in dichloromethane. The resultant solution was washed withbrine, dried over sodium sulfate, and concentrated under reducedpressure to give 2-(3,4-dichlorophenyl)oxirane (1.79 g, 50% crude). Thecrude product was used in the next step without further purification: ¹HNMR (CDCl₃, 500 MHz) 7.41 (d, J=8.5 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H),7.12 (dd, J=8.5, 2.0 Hz, 1H), 3.81 (dd, J=4.0, 2.5 Hz, 1H), 3.14 (dd,J=5.5, 4.0 Hz, 1H), 2.73 (dd, J=5.5, 2.5 Hz, 1H); ESI MS m/z 189 [M]+.

Step C: A solution of 1,1-dimethyl-3′-bromobenzyl amine (1.18 g, 5.51mmol) which was prepared in Step A, and the epoxide from Step B (0.95 g,5.02 mmol) in ethanol (10 mL) was heated at 90° C. for 17 hours. Themixture was concentrated under reduced pressure. The crude product waspurified by flash column chromatography (0 to 100% ethyl acetate inhexanes) to afford2-(2-(3-bromophenyl)propan-2-ylamino)-1-(3,4-dichlorophenyl)ethanol(1.46 g, 72%): ¹H NMR (CDCl₃, 500 MHz) δ 7.51 (d, J=2.0 Hz, 1H),7.45-7.34 (m, 4H), 7.20 (t, J=8.0 Hz, 1H), 7.12 (dd, J=2.0, 8.5 Hz, 1H),4.54 (dd, J=3.5, 8.5 Hz, 1H), 3.49 (s, 1H), 2.65 (dd, J=12.5, 3.5 Hz,1H); 2.35 (dd, J=12.5, 8.5 Hz, 1H), 1.58 (s, 1H), 1.47 (s, 3H), 1.46 (s,3H); ESI MS m/z 404 [M+H]⁺.

Step D: To an ice-cooled solution of the alcohol (920 mg, 2.49 mmol)from Step C above in dichloromethane (60 mL) was added concentratedsulfuric acid (6 mL) drop-wise. The reaction solution was stirred at 0°C. for 5 hours, and then was added slowly to ice-cold saturated sodiumbicarbonate. The organic layer was separated and the aqueous layer wasextracted with dichloromethane (2×). The combined organic extracts werewashed with brine, dried over sodium sulfate, and concentrated underreduced pressure. The crude product was purified by flash columnchromatography (10 to 40% ethyl acetate in hexanes) to give7-bromo-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline(431 mg, 33%): ¹H NMR (CDCl₃, 500 MHz) δ 7.40 (d, J=2.0 Hz, 1H), 7.36(d, J=8.0 Hz, 1H), 7.22 (dd, J=8.0, 2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H),6.88 (dd, J=8.5, 2.0 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 3.96 (t, J=5.5 Hz,1H), 3.38 (dd, J=13.5, 5.0 Hz, 1H), 3.03 (dd, J=13.5, 5.5 Hz, 1H), 1.51(s, 3H), 1.47 (s, 4H); ESI MS m/z 386 [M+H]⁺.

Step E: To a solution of the product (535 mg, 1.39 mmol) from Step D indimethyl sulfoxide (20 mL), was added bis(pinacolato)diboron (423 mg,1.67 mmol) and potassium acetate (409 mg, 4.17 mmol). The resultantsolution was purged with argon for 10 minutes, and thendichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (114 mg, 0.14 mmol) was added. The reactionsolution was further deoxygenated with argon for 5 minutes and heated at80° C. for 2 hours. The reaction solution was then cooled to roomtemperature, diluted with ethyl acetate, washed with brine, dried oversodium sulfate, and concentrated under reduced pressure to afford4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline(557 mg, crude) which was used in the next step without furtherpurification: ESI MS m/z 433 [M+H]⁺.

Step F: 6-Bromo-[1,2,4]triazolo[1,5-a]pyridine (600 mg, 3.03 mmol) wasadded to a mixture of the boronate ester from step E (873 mg, 1.68mmol), cesium carbonate (1.97 g, 6.06 mmol) in DMF (60 mL) and water (12mL). The reaction mixture was deoxygenated with argon.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (82 mg, 0.10 mmol) was added and the reactionmixture was stirred at 90° C. for 1 hour, cooled, diluted with water,and extracted with dichloromethane (3×). The combined organic extractswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated. Purification by flash column chromatography (0 to 100%90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solutionin dichloromethane) gave the desired4-(3,4-dichlorophenyl)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline(431 mg, 50% over 2 steps): ¹H NMR (CDCl₃, 500 MHz) ¹H NMR (CDCl₃, 500MHz) δ 8.79 (s, 1H), 8.38 (s, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.77 (dd,J=8.0, 1.5 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.31 (dd,J=8.0, 1.5 Hz, 1H)), 7.21 (d, J=1.5 Hz, 1H), 6.99-6.92 (m, 2H), 4.08 (t,J=5.5 Hz, 1H), 3.45 (dd, J=13.5, 5.5 Hz, 1H), 3.10 (dd, J=13.5, 5.5 Hz,1H), 1.68 (s, 3H), 1.60 (s, 1H), 1.57 (s, 3H); ESI MS m/z 423 [M+H]⁺.

Example 41 Primary Binding Assay Preparation of Membranes

Recombinant HEK-293 cells expressing either the hSERT, hDAT, or hNETproteins were harvested from T-175 flasks as follows. The medium wasremoved from the flasks and the cells rinsed with HBSS without Ca andwithout Mg. The cells were then incubated for 5-10 minutes in 10 mMTris-Cl, pH 7.5, 5 mM EDTA before the cells were lifted with acombination of pipetting and scraping, as needed. The cell suspensionwas collected into centrifuge bottles and homogenized for 30 secondswith a Polytron homogenizer. The suspension was centrifuged for 30minutes at 32,000×g, 4° C. The supernatant was decanted and the pelletresuspended and homogenized in 50 mM Tris-Cl, pH 7.5, 1 mM EDTA for 10seconds. The suspension was then centrifuged again for 30 minutes at32,000×g, 4° C. The supernatant was decanted and the pellet resuspendedin 50 mM Tris-Cl, pH 7.5, 1 mM EDTA and briefly homogenized. A Bradfordassay (Bio-rad) was performed and the membrane preparation diluted to 2mg/ml with 50 mM Tris-Cl, pH 7.5, 1 mM EDTA. Aliquots were prepared, andthen frozen and stored at −80° C.

SERT Radioligand Binding Assay

Compounds were dissolved in 100% DMSO at a concentration 100 times thedesired highest assay concentration, serially diluted 1:3 in 100% DMSO,and 0.4 μl/well of each solution was dispensed to a Nunc polypropylene,round bottom, 384-well plate. 100% inhibition is defined with 0.4μl/well of 1 mM fluoxetine dissolved in DMSO. 20 μl/well of a 2×membrane preparation (15 ug/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) and 20 μl/well of a 2× radioligand solution (520 pM [¹²⁵I]RTI-55in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KCl) were added to each welland the reaction incubated for 1 hour at room temperature. The contentsof the assay plate were then transferred to a MilliporeMultiscreen_(HTS) GF/B filter plate which was pretreated with 0.5% PEIfor at least one hour. The plate was vacuum filtered and washed with 7washes of 100 μl/well 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KClchilled to 4° C. The filtration and washing were completed in less than90 seconds. The plates were air-dried overnight, 12 μl/well ofMicroScint scintillation fluid added, and the plates counted in aTrilux.

DAT Radioligand Binding Assay

Compounds were dissolved in 100% DMSO at a concentration 100 times thedesired highest assay concentration, serially diluted 1:3 in 100% DMSO,and 0.4 μl/well of each solution was dispensed to a Nunc polypropylene,round bottom, 384-well plate. 100% inhibition is defined with 0.4μl/well of 1 mM GBR-12935 dissolved in DMSO. 20 ul/well of a 2× membranepreparation (12.5 μg/ml in 30 mM sodium phosphate buffer, pH 7.9 at 4°C.) and 20 μl/well of a 2× radioligand solution (250 μM [¹²⁵I]RTI-55 in30 mM sodium phosphate buffer, pH 7.9 at 4° C.) were added to the welland the reaction incubated for 1 hour at room temperature. The contentsof the assay plate were then transferred to a MilliporeMultiscreen_(HTS) GF/B filter plate which was pretreated with 0.5% PEIfor at least one hour. The plate was vacuum-filtered and washed with 7washes of 100 μl/well 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KClchilled to 4° C. The filtration and washing were completed in less than90 seconds. The plates were air-dried overnight, 12 μl/well ofMicroScint scintillation fluid added, and the plates counted in aTrilux.

NET Radioligand Binding Assay

Compounds were dissolved in 100% DMSO at a concentration 100 times thedesired highest assay concentration, serially diluted 1:3 in 100% DMSO,and 1.0 μl/well of each solution was dispensed to a Nunc polypropylene,round bottom, 384-well plate. 100% inhibition is defined with 1.0μl/well of 10 mM desipramine dissolved in DMSO. 50 μl/well of a 2×membrane preparation (0.4 mg/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) and 50 μl/well of a 2× radioligand solution (4 nM [³H]nisoxetinein 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KCl) were added to the welland the reaction incubated for 1 hour at room temperature. The contentsof the assay plate were then transferred to a MilliporeMultiscreen_(HTS) GF/B filter plate which was pretreated with 0.5% PEIfor at least one hour. The plate was vacuum filtered and washed with 7washes of 100 μl/well 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KClchilled to 4° C. The filtration and washing were completed in less than90 seconds. The plates were air-dried overnight, 12 μl/well ofMicroScint scintillation fluid added, and the plates counted in aTrilux.

Data Analysis

The raw data was normalized to percent inhibition using control wellsdefining 0% (DMSO only) and 100% (selective inhibitor) inhibition whichwere run on each plate. Each plate was run in triplicate, and theconcentration response curve thus generated was fit using thefour-parameter dose response equation,Y=Bottom+(Top-Bottom)/(1+10^((LogIC₅₀−X)*HillSlope)) in order todetermine the IC₅₀ value for each compound. The radioligandconcentration chosen for each assay corresponds to the K_(d)concentration determined through saturation binding analysis for eachassay.

Example 42 Occupancy Assay

The general procedure for brain tissue collection and transporteroccupancy assessment is briefly described as follows. Mice weresacrificed by asphyxiation in CO₂, rats by decapitation and dogs by IVinjection of euthanasia solution. For mice and rats, after the brainswere removed from the skull, the forebrain tissue (removal of thebrainstem and cerebellum) was used for SERT, NET, and DAT occupancyassessment. In dogs, the striatum was dissected for DAT occupancy andthe remaining forebrain tissue (without the striatum, brainstem, andcerebellum) was used for SERT and NET occupancy assessment. The braintissues were frozen in chilled isopentane and stored at −80° C. untilhomogenization.

The brain tissues were thawed and then homogenized using a polytronhomogenizer (Kinematica). Sample aliquots were frozen immediately andstored at −80° C. Protein content was measured for each sample using aCoomassie protein assay kit (Pierce).

On the day of ex vivo binding for occupancy assessment, frozen samplealiquots were thawed and needle homogenized, and 100 μg of the tissuewas incubated for SERT, NET, and DAT binding under assay conditionssummarized in Table 2. After incubation, the reactions were terminatedby the addition of ice-cold assay buffer and rapid filtration through aBrandel Cell Harvester using FPXLR-196 filters. The filters were washedtwice with ice-cold incubation buffer, punched into a clear plate priorto the addition of 200 ul scintillation fluid per well. Radioligand wasmeasured using a Wallac Microbeta liquid scintillation counter.

TABLE 2 Ex Vivo Binding Assay Conditions for Serotonin, Norepinephrineand Dopamine Transporter Occupancy. Non- Incubation Specific Buffer Timeand Transporter Radioligand Drug (μM) (nM) Temperature SERT 2 nMFluoxetine, Tris, 50 10 minutes [³H]Citalopram 10 NaCl, 120 at 4° C.KCl, 5 DAT 0.1 nM GBT-12935, Soduim 10 minutes [¹²⁵I]RTI-55 10 phosphateat 4° C. (+0.5 μM) buffer, 30 citalopram) NET 5 nM Reboxetine, Tris, 5020 minutes [³H]-Nisoxetine 10 NaCl, 300 at 4° C. KCl, 5

The specific binding was calculated by subtracting the value of thenon-specific binding from that of the total binding in each sample. Thepercent occupancy was calculated as (1−specific binding in drugtreated/specific binding in vehicle treated)×100%. For estimation of invivo occupancy EC₅₀ (total plasma concentration of compound producing50% occupancy), plots of occupancy values versus plasma concentrationswere fitted to a one-site binding model using nonlinear regressionaccording to the following equation: % Occupancy=Emax*C/(EC₅₀+C) whereEmax is the maximal specific binding, C is the drug concentration, andEC₅₀ is the total plasma concentration required for 50% binding siteoccupancy. Nonlinear regression was performed using GraphPad Prismversion 3.00 (GraphPad Software, San Diego, Calif.).

The results are shown in Table 3, below:

TABLE 3 IC₅₀ and Occupancy Data SERT DAT NET Occupancy Occupancy IC50IC50 IC50 SERT DAT NET Dose time point Example (nM) (nM) (nM) Occupancy% Occupancy % Occupancy % (mg/kg) (h) 1 27.9 64.5 174.2 2 143.6 89.4360.4 3 53.8 90.5 150.1 4 21.4 138.4 47.3 5 15.8 31.2 63.1 6 35%*  9%*0%* 7 35%* 16%* 0%* 8 59%* 30%* 49%*  9 4.8 1.8 132.7 60 71 20 1 1 1026.0 28.0 549.0 11 10 80 13 12 3.6 50.2 18.8 82 15 46 1 3 13 2.3 2.4 9755 53 5 3 3 15 14.0 213.0 86.0 16 20.0 77.0 13.0 17 6.9 84.7 421.3 186.1 29.9 131.5 22 39.0 37.0 63.0 23 83.6 101.0 282.9 25 4.9 47.3 194.950 0 0 1 3 26 24.5 5.8 23.3 29 29.7 78.3 34.1 30 100.7 24.5 214.8 3115.9 33.0 9.8 33 6.2 15.4 26.4 49 8 3 1 1 34 1.8 7.1 22.9 10 0 11 1 1 3561.1 80.2 1015.0 36 1.8 30.8 26.0 75 26 11 1 3 39 14.1 83.2 70.4 40 4.22.1. 51 74 78 1 3 3 *% Inhibition @ 100 nM. All binding data are for(+)-enantiomers.

Example 43 In Vivo Behavioral Assays

For All Tests

All animals were maintained in accordance with the guidelines of theCommittee on Animals of the Bristol-Myers Squibb Company and Guide forCare and Use of Laboratory Animals, Institute of Animal LaboratoryResources, 1996, which are hereby incorporated by reference in theirentirety. Research protocols were approved by the Bristol-Myers SquibbCompany Institutional Animal Care and Use Committee.

Mouse Tail Suspension Assay

Male Swiss Webster mice were housed 3-4 per cage in rooms maintained ata constant temperature (21-23° C.) and humidity (50±10%) on a 12-hourlight/dark cycle. Animals had ad libitum access to water and foodthroughout studies. On the day of testing, they were brought into thetesting room and allowed to acclimate for one hour.

To begin testing, the tail was attached to a piece of tape which iasthen attached to a hook on the ceiling of a sound-attenuated chamber.Immobility was automatically recorded using the Med Associates software.Compounds were administered acutely at a fixed pretreatment intervalbefore session.

The minimum effective dose of Example 36-(+)-enantiomer in the mousetail suspension study was 10 mg/kg.

Rat Forced Swim Assay

Male Sprague Dawley rats are housed in pairs in rooms maintained at aconstant temperature (21-23° C.) and humidity (50±10%) on a 12-hourlight/dark cycle. Animals have ad libitum access to water and foodthroughout studies. Animals are handled for two minutes each on the twodays prior to the start of the experiment. On the first day of testing,rats are placed in the swim tank (a Pyrex cylinder 46 cm tall×21 cm indiameter, filled with 30 cm of water ranging between 24-26° C.) for 15minutes (the pre-swim session). At the end of the 15-minute session,rats are dried and replaced in their home cage. Compounds areadministered at three time points in the next 24 hour (23.5, 5, and 1hour), prior to a second test swim. This swim test is 5 minutes induration and the animals' behavior is videotaped and active behaviors(immobility, swimming, climbing) are scored. At the end of each 5-secondperiod during the 5-minute test session the rat's behavior is scored asone of the following: immobility (the rat remained floating in the waterwithout struggling and made only those movements necessary to keep itshead above water), swimming (the rat made active swimming motions, morethan necessary to merely maintain its head above water, e.g., movingaround in the cylinder), or climbing (the rat made active movements withits forepaws in and out of the water, usually directed against thecylinder wall). Compounds are only identified by a predesignated codeand the experimenter remains blinded throughout the experiment(including while scoring videotapes).

Rat and Mouse Locomotor Activity

Animals are housed according to conditions described above for the twospecies. The testing apparatus consisted of Plexiglas chambers equippedwith Digiscan activity monitors (Omnitech Electronics, Columbus, Ohio)that detect interruptions of eight photobeams. Horizontal activity wasrecorded in 5-minute bins for a total of 60 minutes and expressed astotal distance covered (in cm). Compounds were administered acutely at afixed pretreatment interval prior to testing.

Example 44 Preparation of single crystals of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolineL-tartrate (L-tartrate salt)

(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolineL-tartrate salt (20 mg) was dissolved in methanol (8 mL) under heatingin a vial. Distilled water (2 ml) was then added to the above clearsolution. The resulting solution was capped and placed at roomtemperature. Needle-like crystals of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolineL-tartrate salt were obtained after slow evaporation in air within days.

Example 45 Preparation of single crystals of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemonohydrochloride monoisopropanolate monohydrate (HCl salt; Form SA-1)

(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemono-HCl salt (20 mg) was dissolved in isopropanol (10 mL) under heatingin a vial. Distilled water (2 mL) was then added to the above clearsolution. The resulting solution was capped and placed at roomtemperature. Long needle crystals of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemono-HCl monoisopropanolate monohydrate salt were obtained after slowevaporation in air within days.

Example 46 Preparation of single crystals of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemonohydrochloride (HCl salt; Form N-2)

(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemono-HCl salt (20 mg) was dissolved in methanol (8 mL) under heating ina vial. Distilled water (2 mL) was then added to the above clearsolution. The resulting solution was capped and placed at roomtemperature. Needle like single crystals of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemono-HCl salt were obtained after slow evaporation in air within days.

Example 47 Single Crystal Analysis by X-Ray Crystallography

The data of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolineL-tartrate (L-tartrate salt) and(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemonohydrochloride (HCl salt; Form N-2) crystals were collected on aSMART CCD diffractometer equipped with graphite-monochromated Cu Kαradiation (λ=1.54178 Å) at 225K and the room temperature, respectively.The data of(S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemonohydrochloride monoisopropanolate monohydrate (HCl salt; Form SA-1)were collected on an X8-ApexII diffractometer equipped withgraphite-monochromated Cu Kα radiation (λ=1.54178 Å) at room temperature(APEX-II 1.0-28, Data Collection Software for Bruker CCD devices. BrukerAXS Inc., Madison, Wis., US. SAINT PLUS, Processing Software forBrukerCCD devices, Bruker AXS Inc., Madison, Wis., US). The final unitcell parameters were determined using the entire data set.

All structures were solved by direct methods and refined by thefull-matrix least-squares techniques, using the SHELXTL software package(Sheldrick, GM. 1997, SHELXTL. Structure Determination Programs. Version5.10, Bruker AXS, Madison, Wis., USA.). The function minimized in therefinements was Σ_(w)(|F_(o)|−|F_(c)|)². R is defined asΣ∥F_(o)|−|F_(c)∥/Σ|F_(o)| whileR_(w)=[Σ_(w)(|F_(o)|−|F_(c)|)₂/Σ_(w)|F_(o)|²]^(1/2), where w is anappropriate weighting function based on errors in the observedintensities. Difference Fourier maps were examined at all stages ofrefinement. In L-tartrate form, one of chloro atoms on pendant phenylring is disordered over two positions with 50% occupancy ratio each. Thetartaric acid molecule is also disordered, which could not be modeledwell. The numbers of methanol molecules could not be identified due todisorder. All non-hydrogen atoms were refined with anisotropic thermaldisplacement parameters. The hydrogen atoms associated with hydrogenbonding were located in the final difference Fourier maps while thepositions of the other hydrogen atoms were calculated from an idealizedgeometry with standard bond lengths and angles. They were assignedisotropic temperature factors and included in structure factorcalculations with fixed parameters.

The crystal data of the L-tartrate salt form is shown in Table 4 and thefractional atomic coordinates are listed in Table 5. The crystal data ofForm SA-1 is shown in Table 6 and the fractional atomic coordinates arelisted in Table 7. The crystal data of Form N-2 is shown in Table 8 andthe fractional atomic coordinates are listed in Table 9. It should beunderstood by one of ordinary skills in the art that slight variationsin the coordinates are possible and are considered to be within thescope the present disclosure.

TABLE 4 Crystal Data of L-tartrate Form Empirical formula C40H40Cl2N8O8Formula weight 831.70 Temperature 225(1) K Wavelength 1.54178 Å Crystalsystem, space group Orthorhombic, C222₁ Unit cell dimensions a =7.6264(10) Å alpha = 90 deg. b = 38.942(5) Å beta = 90 deg. c =24.449(3) Å gamma = 90 deg. Volume 7261.1(16) Å³ Z, Calculated density8, 1.522 Mg/m³ Absorption coefficient 2.195 mm⁻¹ F(000) 3472 Theta rangefor data collection 2.27 to 66.20 deg. Limiting indices −8 <= h <= 8,−45 <= k <= 42, −22 <= 1 <= 28 Reflections collected/unique 24815/6156[R(int) = 0.1027] Refinement method Full-matrix least-squares onF{circumflex over ( )}2 Data/restraints/parameters 6156/2/323Goodness-of-fit on F{circumflex over ( )}2 2.340 Final R indices [I >2sigma(I)] R1 = 0.2345, wR2 = 0.4418 R indices (all data) R1 = 0.3127,wR2 = 0.4595 Absolute structure parameter 0.00(11) Extinctioncoefficient 0.0075(9) Largest diff. peak and hole 0.991 and −0.773 e.Å⁻³

TABLE 5 Atomic Coordinates of L-tartrate Form Atomic coordinates (×10⁴)and equivalent isotropic displacement parameters (Å² × 10³) forL-tartrate Form. U(eq) is defined as one third of the trace of theorthogonalized Uij tensor. x y z U(eq) Cl(1) 8174(9)    94(1) 4057(2)171(2) Cl(2′) 5256(12)  −323(2) 4561(3) 137(3) Cl(2) 11696(16)   −83(2)4303(4) 201(6) C(1) 8480(30)  −296(3) 4374(6) 109(5) C(2) 10110(40)  −377(4) 4452(8) 149(8) C(3) 10610(20)   −698(5) 4682(7) 136(6) C(4)9280(20)  −919(2) 4902(4)  78(3) C(5) 7540(20)  −803(3) 4839(5) 107(4)C(6) 7210(20)  −477(3) 4556(5) 109(5) C(7) 9651(19) −1252(2) 5194(5) 97(4) C(8) 8790(20) −1532(3) 4886(5) 122(5) C(9) 7840(20) −1835(2)5751(6) 111(5) C(10) 8275(16) −1504(3) 6055(6)  87(3) C(11) 9041(16)−1238(2) 5781(5)  83(3) C(12) 9409(14)  −941(2) 6125(5)  71(3) C(13)8887(15)  −937(3) 6658(6)  82(3) C(14) 8050(16) −1194(3) 6915(5)  75(3)C(15) 7808(18) −1500(2) 6586(6)  90(4) C(16) 7563(15) −1182(2) 7472(6) 79(3) C(17) 6993(17)  −875(4) 7699(6)  96(4) C(18) 6487(18) −1113(4)8577(8) 100(4)  C(19) 7058(19) −1442(5) 8390(5) 112(5)  C(20) 7492(19)−1472(3) 7861(7) 118(5)  C(21) 5610(30)  −748(9) 8994(6) 194(13) C(22)7820(20) −2663(4) 4481(6) 124(4)  O(3) 10030(30)  −2275(4) 4338(6)225(7)  C(23) 9000(20) −2557(4) 4090(6) 119(4)  O(2) 7170(20) −2487(3)4903(5) 170(4)  O(1) 7230(20) −2972(3) 4484(5) 186(5)  N(1) 8830(20)−1870(2) 5245(6) 138(5)  N(2) 6491(14)  −849(3) 8247(6) 109(4)  N(3)5890(20) −1046(4) 9099(9) 150(7)  N(4) 5882(18)  −566(3) 8552(6) 119(4) O(8) −840(20)   53(4) 2431(8) 235(7)  O(1W) 9327(17) −3528(3) 4909(5)175(4)  C(74)  450(50) −1233(9)  3340(13) 272(14) O(9) −2350(140) −964(16)  3320(30) 630(40) O(4) 7600(60) −2153(9)  3690(14) 400(15)O(6) 10620(40)  −2645(6) 3106(9) 291(9)  C(72) −2920(80)   −1321(14) 3380(20) 400(30) O(7) −160(50)  −761(8)  3131(12) 351(13) C(70) −300(120)  −361(12)  2710(20) 420(30) C(25) 9840(80)  −2305(16) 3320(20) 440(30) O(5) 8080(40) −2558(7) 2969(9) 312(11) C(24) 8360(40)−2552(8)  3522(10) 241(11) H(3A) 11778 −764 4690 164 H(5A) 6612 −9314976 128 H(7A) 10920 −1291 5191 116 H(8A) 9408 −1570 4544 146 H(8B) 7592−1469 4803 146 H(9A) 8097 −2030 5986 133 H(9B) 6598 −1839 5669 133H(12A) 10003 −753 5980 85 H(13A) 9130 −740 6861 99 H(15A) 7325 −16956744 108 H(17A) 6943 −680 7479 115 H(19A) 7126 −1628 8627 134 H(20A)7766 −1689 7730 142 H(21A) 5111 −624 9280 233 H(1A) 8376 −2045 5049 166H(1B) 9947 −1923 5325 166

TABLE 6 Crystal Data of HCl salt: Form SA-1 Empirical formulaC24H26Cl3N4O2 Formula weight 508.84 Temperature 298(2) K Wavelength1.54178 A Crystal system, space group Monoclinic, P2₁ Unit celldimensions a = 11.0668(9) Å alpha = 90 deg. b = 7.3750(6) Å beta =100.594(7) deg. c = 15.3927(14) Å gamma = 90 deg. Volume 1234.90(18) Å³Z, Calculated density 2, 1.363 Mg/m³ Absorption coefficient 3.595 mm⁻¹F(000) 530 Theta range for data 4.06 to 61.98 deg. collection Limitingindices −12 <= h <= 12, −7 <= k <= 6, −17 <= 1 <= 15 Reflectionscollected/ 3911/2687 [R(int) = 0.0253] unique Completeness to 89.5%theta = 61.98 Refinement method Full-matrix least-squares onF{circumflex over ( )}2 Data/restraints/parameters 2687/1/306Goodness-of-fit on F{circumflex over ( )}2 1.035 Final R indices [I > R1= 0.0382, wR2 = 0.0994 2sigma(I)] R indices (all data) R1 = 0.0423, wR2= 0.1027 Absolute structure 0.02(2) parameter Largest diff. peak andhole 0.270 and −0.201 e. Å⁻³

TABLE 7 Atomic Coordinates of HCl salt: Form SA-1 Atomic coordinates(×10⁴) and equivalent isotropic displacement parameters Å² × 10³) forForm SA-1. U(eq) is defined as one third of the trace of theorthogonalized Uij tensor. x y z U(eq) Cl 12265(1)  6142(1) 1683(1)49(1) Cl(1) 7875(1) 12955(2)  4765(1) 82(1) Cl(2) 8143(1) 9869(2)6212(1) 87(1) N(1) 2603(2) 8917(4) −585(2) 34(1) N(2) 10328(2)  9284(4)1422(2) 39(1) C(3) 7992(3) 8350(5) 1854(2) 31(1) C(4) 6974(3) 8951(5) 360(2) 32(1) N(5) 1421(3) 9376(5) −494(2) 47(1) C(6) 5842(3) 8414(5) 549(2) 32(1) C(7) 4724(3) 8458(5) −145(2) 32(1) C(8) 8036(3) 8902(5) 998(2) 31(1) C(9) 3613(3) 8927(5)  63(2) 36(1) C(10) 9143(3) 8296(5)2564(2) 35(1) N(11) 1476(3) 8685(5) −1929(2)  51(1) C(12) 5807(3)7820(6) 1405(2) 37(1) C(13) 8878(3) 8695(5) 3475(2) 37(1) C(14) 6859(3)7787(6) 2035(2) 38(1) C(15) 4772(3) 8039(5) −1033(2)  41(1) C(16)10107(3)  9607(5) 2333(2) 38(1) C(17) 2614(3) 8532(5) −1448(3)  39(1)C(18) 9221(3) 9458(6)  715(2) 42(1) C(19) 8304(4) 10787(6)  4526(3)47(1) C(20) 8550(3) 10430(5)  3699(3) 42(1) C(21) 3747(4) 8064(6)−1674(2)  46(1) C(22)  821(3) 9193(6) −1314(3)  50(1) C(23) 8957(4)7332(6) 4108(3) 48(1) C(24) 8714(4) 7701(7) 4937(3) 55(1) C(25) 8399(4)9426(8) 5162(3) 58(1) OW1 12197(4)  11835(6)  1559(3) 63(1) O(01)13401(5)  9513(6) 2783(4) 138(2)  C(01) 14893(7)   7959(17) 3801(5)166(5)  C(02) 14430(8)   9598(14) 3370(6) 139(3)  C(03) 14517(9) 11360(20) 3818(8) 221(8)  H(2A) 10639 8162 1397 46 H(2B) 10900 100761311 46 H(4A) 7017 9351 −207 38 H(9A) 3554 9248 638 43 H(10A) 9484 70682573 42 H(12A) 5066 7445 1549 44 H(14A) 6817 7377 2600 46 H(15A) 55247738 −1183 49 H(16A) 9829 10844 2381 45 H(16B) 10871 9453 2750 45 H(18A)9335 8717 216 50 H(18B) 9148 10709 518 50 H(20A) 8495 11359 3285 50H(21A) 3795 7776 −2255 55 H(22A) −20 9407 −1461 60 H(23A) 9175 6163 397058 H(24A) 8763 6773 5351 66 HW1 12650(50) 11440(80) 1990(40)   67(19)HW2 12190(50)  12930(110) 1710(40)   90(20) H(01D) 13362 8533 2528 207H(01A) 14782 6981 3382 249 H(01B) 14456 7696 4270 249 H(01C) 15752 80984041 249 H(02A) 15024 9777 2977 167 H(03A) 14198 12289 3401 331 H(03B)15361 11617 4062 331 H(03C) 14047 11331 4284 331

TABLE 8 Crystal Data of HCl salt: Form N-2 Empirical formula C21H17Cl3N4Formula weight 431.74 Temperature 298(2) K Wavelength 1.54178 Å Crystalsystem, space group Orthorhombic, P2₁2₁2₁ Unit cell dimensions a =7.1183(2) Å alpha = 90 deg. b = 21.2160(7) Å beta = 90 deg. c =26.3602(9) Å gamma = 90 deg. Volume 3981.0(2) Å³ Z, Calculated density8, 1.441 Mg/m³ Absorption coefficient 4.283 mm⁻¹ F(000) 1776 Crystalsize 0.16 × 0.07 × 0.06 mm Theta range for data collection 2.67 to 44.53deg. Limiting indices −6 <= h <= 5, −19 <= k <= 18, −23 <= 1 <= 23Reflections collected/unique 9626/2985 [R(int) = 0.0700] Completeness totheta = 44.53 95.3% Data/restraints/parameters 2985/0/505Goodness-of-fit on F{circumflex over ( )}2 1.031 Final R indices [I >2sigma(I)] R1 = 0.0580, wR2 = 0.1446 R indices (all data) R1 = 0.0780,wR2 = 0.1669 Absolute structure parameter 0.10(4) Largest diff. peak andhole 0.260 and −0.278 e. Å⁻³

TABLE 9 Atomic Coordinates of HCl salt: Form N-2 Atomic coordinates(×10⁴) and equivalent isotropic displacement parameters (Å² × 10³) forForm N-2. U(eq) is defined as one third of the trace of theorthogonalized Uij tensor. x y z U(eq) Cl(1) 4498(5)  2054(2) 5726(1)84(1) Cl(2) 8606(6)  2604(2) 5897(1) 98(1) Cl(3) 13423(5)  8143(1)1794(1) 75(1) Cl(4) 9097(4)  8448(1) 1988(1) 73(1) Cl(5) −2074(4) 5119(1) 4228(1) 71(1) Cl(6) 3031(4)  5078(1) 2983(1) 66(1) N(1) 2223(11)4893(4) 4125(3) 52(2) N(2)  61(15) 7409(6) 6214(5) 64(3) N(3) −573(13)7985(6) 6078(5) 65(3) N(4) −306(16) 7936(6) 6927(5) 75(4) N(5) 7228(10)5382(4) 3091(3) 47(2) N(6) 9780(14) 2724(5) 1073(5) 56(3) N(7)10462(14)  2158(6) 1235(4) 62(3) N(8) 10074(16)  2166(6)  367(4) 70(3)C(1) 3750(20) 3157(6) 5294(4) 67(4) C(2) 5220(20) 2801(5) 5526(4) 62(4)C(3) 6990(20) 3065(8) 5577(5) 75(4) C(4) 7330(20) 3646(7) 5390(5) 75(5)C(5) 5980(20) 3987(6) 5149(5) 67(4) C(6) 4180(20) 3750(6) 5092(4) 57(4)C(7) 2634(17) 4168(5) 4848(4) 53(3) C(8) 3267(15) 4321(5) 4307(4) 54(3)C(9) 2762(18) 5465(5) 4424(5) 63(4) C(10) 2298(13) 5348(6) 4977(5) 44(3)C(11) 2294(14) 4749(5) 5175(5) 42(3) C(12) 1796(17) 4667(5) 5682(5)57(3) C(13) 1424(16) 5177(6) 5975(5) 57(3) C(14) 1510(15) 5791(5)5785(5) 45(3) C(15) 1928(14) 5865(5) 5284(5) 44(3) C(16) 1095(14)6353(6) 6107(5) 44(3) C(17)  466(16) 6920(7) 5908(5) 52(3) C(18)−747(19) 8258(7) 6533(8) 79(5) C(19)  230(20) 7382(8) 6719(8) 79(4)C(20)  856(16) 6812(7) 6955(5) 61(3) C(21) 1241(15) 6307(6) 6639(6)58(4) C(31) 11260(20)  6456(5) 2095(5) 68(4) C(32) 12471(16)  6939(6)1978(4) 63(4) C(33) 11878(19)  7564(6) 1953(4) 61(3) C(34) 9939(18)7684(5) 2033(4) 55(3) C(35) 8744(17) 7205(5) 2162(4) 51(3) C(36)9370(18) 6600(5) 2199(4) 52(3) C(37) 8002(17) 6074(5) 2356(4) 49(3)C(38) 8399(14) 5938(5) 2920(4) 51(3) C(39) 7870(18) 4792(5) 2834(5)60(4) C(40) 8081(17) 4873(6) 2263(5) 53(3) C(41) 8178(17) 5465(5)2060(5) 52(3) C(42) 8419(18) 5507(5) 1536(6) 66(4) C(43) 8611(16)4964(7) 1238(4) 59(3) C(44) 8532(16) 4370(6) 1459(5) 54(3) C(45)8220(17) 4337(5) 1978(5) 57(3) C(46) 8796(17) 3796(6) 1143(5) 54(3)C(47) 9454(16) 3252(7) 1367(5) 56(3) C(48) 10601(16)  1851(6)  794(7)67(4) C(49) 9511(17) 2725(6)  563(7) 55(4) C(50) 8909(16) 3292(7) 321(5) 62(4) C(51) 8534(16) 3805(6)  614(6) 53(3) H(1A) 2481 4958 379562 H(1C) 979 4827 4155 62 H(5A) 7327 5336 3429 56 H(5C) 6012 5453 301656 H(1B) 2535 2999 5277 81 H(4B) 8526 3818 5427 90 H(5B) 6262 4384 502180 H(7B) 1466 3924 4831 63 H(8B) 4609 4401 4302 65 H(8C) 3009 3966 408665 H(9A) 2075 5829 4301 76 H(9B) 4095 5547 4386 76 H(12A) 1718 4264 581868 H(13A) 1102 5116 6313 69 H(15A) 1967 6267 5145 52 H(17A) 322 69625559 62 H(18A) −1175 8671 6562 94 H(20A) 998 6783 7305 73 H(21A) 16075926 6783 70 H(31A) 11679 6042 2104 81 H(32A) 13726 6845 1914 76 H(35A)7486 7294 2226 62 H(37A) 6713 6232 2322 59 H(38A) 9722 5846 2967 61H(38B) 8090 6306 3123 61 H(39A) 6970 4458 2901 71 H(39B) 9067 4664 297671 H(42A) 8454 5901 1382 79 H(43A) 8793 5002 890 71 H(45A) 8104 39452133 69 H(47A) 9678 3241 1714 67 H(48A) 11041 1439 779 80 H(50A) 87773311 −30 74 H(51A) 8094 4171 460 63

Example 48 Powder X-Ray Diffraction for Forms SA-1 and N-2

X-ray powder diffraction (PXRD) data were obtained using a Bruker C2GADDS. The radiation was Cu Kα (40 KV, 40 MA). The sample-detectordistance was 15 cm. Powder samples were placed in sealed glasscapillaries of 1 mm or less in diameter; the capillary was rotatedduring data collection. Data were collected for 3<20<35° with a sampleexposure time of at least 1000 seconds. The resulting two-dimensionaldiffraction arcs were integrated to create a traditional 1-dimensionalPXRD. The results of the PXRD pattern and a simulated pattern calculatedfrom the single crystal data are shown in FIG. 1.

Table 10 lists the characteristic PXRD peaks that describe Form SA-1((S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemonohydrochloride monoisopropanolate monohydrate) and Form N-2((S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinemonohydrochloride). In particular, Table 10 shows characteristicdiffraction peak positions (degrees 20±0.1) at room temperature, basedon a high quality pattern collected with a diffractometer (cuKα) with aspinning capillary with 20 calibrated with a NIST or other suitablestandard.

TABLE 10 Form SA-1 Form N-2 5.8 8.3 8.1 8.9 9.1 10.9 10.8 14.2 11.7 14.713.0 16.7 13.3 17.3 14.5 18.0 15.1 18.4 15.4 18.8 16.2 20.2 16.8 21.9

Example 49 Differential Scanning Calorimetry for Form SA-1

Differential scanning calorimetry (DSC) experiments were performed in aTA Instruments™ model Q1000 or 2920. The sample (about 2-6 mg) wasweighed in a pinpricked hermetically sealed aluminum pan and accuratelyrecorded to a hundredth of a milligram, and transferred to the DSC. Theinstrument was purged with nitrogen gas at 50 mL/min. Data werecollected between room temperature and 300° C. at 10° C. min. heatingrate. The plot was made with the endothermic peaks pointing down. Theresults are shown in FIG. 2.

Example 50 Thermogravimetric Analysis for Form SA-1

The results are shown in FIG. 3.

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions, and the like canbe made without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow.

What is claimed is:
 1. A compound of formula (I):

wherein: the carbon atom designated * is in the R or S configuration; R¹is H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, C₁-C₆ haloalkyl, or gem-dialkyl of which each alkyl isC₁-C₄; R² is H, halogen, —OR¹¹, —S(O)—R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹²,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹R¹⁰; R³ is a heteroaryl selected from the groupconsisting of pyridyl, 2-oxo-pyridin-1-yl, quinolinyl, isoquinolinyl,quinolizinyl, 1H-pyrrolo [2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl,[1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]pyridinyl,thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, and3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or a non-aromatic heterocycleselected from the group consisting of piperidinyl and 2-oxopiperidinyl;wherein the heteroaryl or non-aromatic heterocycle is optionallysubstituted from 1 to 4 times with substituents as defined below in R¹⁴;R⁴, R⁵ and R⁶ and R⁷ are each independently H or are selected from thegroup consisting of halogen, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)—R¹², —CN, —C(O)R¹²,—C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, and wherein each of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from the groupconsisting of C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenyl whichis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰; R⁸ is H, C₁-C₆alkyl, halogen, or OR¹¹; R⁹ and R¹⁰ are each independently H, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹³, phenyl, or benzyl, where phenyl or benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; or R⁹and R¹⁰ are taken together with the nitrogen to which they are attachedto form a piperidine, pyrrolidine, piperazine, N-methylpiperazine,morpholine, or thiomorpholine ring; R¹¹ is H, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—C(O)R¹³, phenyl, or benzyl, where phenyl or benzyl is optionallysubstituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, or C₁-C₄ alkoxy; R¹² is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, orbenzyl, where phenyl or benzyl is optionally substituted 1 to 3 timeswith halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; orR¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring, with the provisothat only one of R⁹ and R¹⁰ or R¹¹ and R¹² are taken together with thenitrogen to which they are attached to form a piperidine, pyrrolidine,piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring; R¹³is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; n is 0, 1, or 2; and R¹⁴ isindependently selected at each occurrence from a substituent selectedfrom the group consisting of halogen, —NO₂, —OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹²,—NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN, —C(O)R¹²,—C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, where C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from the group consisting of C₁-C₃ alkyl, halogen,Ar, —CN, —OR⁹, and —NR⁹R¹⁰, or an oxide thereof, or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein R¹ is H,C₁-C₆ alkyl, or gem-dialkyl of which each alkyl is C₁-C₄.
 3. Thecompound of claim 1, wherein R² is H, halogen, —OR¹¹, —S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.
 4. Thecompound of claim 1, wherein R³ is a heteroaryl selected from the groupconsisting of pyridyl, 2-oxo-pyridin-1-yl, quinolinyl, isoquinolinyl,quinolizinyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl,[1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]pyridinyl,thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, and3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, each of which is optionally andindependently substituted from 1 to 4 times with substituents as definedin R¹⁴.
 5. The compound of claim 1, wherein R³ is a non-aromaticheterocycle selected from the group consisting of piperidinyl and2-oxopiperidinyl, each of which is optionally and independentlysubstituted from 1 to 4 times with substituents as defined in R¹⁴. 6.The compound of claim 1, wherein R⁴ is H, Cl, F, CH₃, OH, or OCH₃. 7.The compound of claim 1, wherein R⁵, R⁶, and R⁷ are each independentlyselected from the group consisting of H, halogen, —OR¹¹, —NR¹¹R¹²,—NR¹¹C(O)R¹², S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, andsubstituted C₁-C₆ alkyl.
 8. The compound of claim 7, wherein R⁷ is H. 9.The compound of claim 8, wherein R⁵ and R⁶ are each H, F, Cl, OH, OCH₃,or CH₃.
 10. The compound of claim 1, wherein R⁸ is H, OH, CH₃, or F. 11.The compound of claim 1, wherein: R¹ is H, C₁-C₆ alkyl, or gem-dialkylof which each alkyl is C₁-C₄; R² is H, halogen, —OR¹¹, —S(O)₂R¹², C₁-C₆alkyl, or substituted C₁-C₆ alkyl; R³ is heteroaryl or non-aromaticheterocycle; R⁴ is H, F, or Cl; and R⁵, R⁶, and R⁷ are eachindependently H, halogen, —OR¹¹, —NR¹¹R¹², —S(O)₂R¹², —C(O)R¹², C₁-C₆alkyl, or substituted C₁-C₆ alkyl.
 12. A compound according to claim 1,selected from the group consisting of:1-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one;4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline;7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;and an oxide thereof, or a pharmaceutically acceptable salt thereof. 13.A compound of formula (I):

wherein: the carbon atom designated * is in the R or S configuration; R¹is H, C₁-C₄ alkyl, or gem-dialkyl of which each alkyl is C₁-C₄; R² is H,halogen, —OR¹¹, —S(O)_(n)R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇cycloalkylalkyl, and wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from the group consisting of C₁-C₃ alkyl, halogen,—CN, —OR⁹, —NR⁹R¹⁰, and phenyl which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,—CN, —OR⁹, or —NR⁹R¹⁰; R³ is [1,2,4]triazolo[1,5-a]pyridine-2-yl,[1,2,4]triazolo[1,5-a]pyridine-5-yl,[1,2,4]triazolo[1,5-a]pyridine-6-yl,[1,2,4]triazolo[1,5-a]pyridine-7-yl, or[1,2,4]triazolo[1,5-a]pyridine-8-yl which is optionally substituted byR¹⁴; R⁴ is H, F, Cl, Me, CN, OR¹¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇ cycloalkylalkyl, and wherein each ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇cycloalkylalkyl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from the groupconsisting of C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenyl whichis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰; R⁵, R⁶, and R⁷ areeach independently H or are selected from the group consisting ofhalogen, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³,—S(O)—R¹², —CN, —C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl, and whereineach of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, andC₄-C₇ cycloalkylalkyl is optionally substituted with from 1 to 3substituents independently selected at each occurrence thereof from thegroup consisting of C₁-C₃ alkyl, halogen, —CN, —OR⁹, —NR⁹R¹⁰, and phenylwhich is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁹, or —NR⁹R¹⁰; R⁸ is H,halogen, OR¹¹ or C¹-C⁴ alkyl; R⁹ and R¹⁰ are each independently H, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹³, phenyl, or benzyl, where phenyl or benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; or R⁹and R¹⁰ are taken together with the nitrogen to which they are attachedto form a piperidine, pyrrolidine, piperazine, N-methylpiperazine,morpholine, or thiomorpholine ring; R¹¹ is H, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—C(O)R¹³, phenyl, or benzyl, where phenyl or benzyl is optionallysubstituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, or C₁-C₄ alkoxy; R¹² is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl orbenzyl, where phenyl or benzyl is optionally substituted 1 to 3 timeswith halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; orR¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, or thiomorpholine ring, with the provisothat only one of R⁹ and R¹⁰ or R¹¹ and R¹² are taken together with thenitrogen to which they are attached to form a piperidine, pyrrolidine,piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring; R¹³is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; n is 0, 1, or 2; and, R¹⁴ isindependently selected at each occurrence from a substituent selectedfrom the group consisting of halogen, —NO₂, —OR¹¹, —NR¹¹R¹²,—NR¹¹C(O)R¹², —NR¹¹C(O)₂R¹², —NR¹¹C(O)NR¹²R¹³, —S(O)_(n)R¹², —CN,—C(O)R¹², —C(O)NR¹¹R¹², C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, and C₄-C₇ cycloalkylalkyl, where C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, and C₄-C₇ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from the group consisting of C₁-C₃ alkyl, halogen,Ar, —CN, —OR⁹, and —NR⁹R¹⁰, or an oxide thereof, or a pharmaceuticallyacceptable salt thereof.
 14. A compound of formula (I):

wherein: the carbon atom designated * is in the R or S configuration; R¹is H, methyl, or gem-dimethyl; R² is H, F, Cl, CN, Me, CF₃, CF₂H, OMe,OCF₃, OCF₂H, or OH; R³ is [1,2,4]triazolo[1,5-a]pyridinyl-6-yl which isoptionally substituted by R¹⁴; R⁴ is H, F, Cl, CN, Me, CF₃, CF₂H, OMe,OCF₃, OCF₂H, or OH; R⁵ to R⁷ is independently, H, F, Cl, CN, Me, CF₃,CF₂H, OMe, OCF₃, OCF₂H, or OH; and R⁸ is H or methyl, or an oxidethereof, a pharmaceutically acceptable salt thereof, a solvate thereof,or a prodrug thereof.
 15. The compound according to claim 14, selectedfrom the group consisting of: 7-([1,2,4] triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;7-([1,2,4] triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;7-([1,2,4] triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;4-(3,4-dichlorophenyl)-7-(5-methyl-[1,2,4] triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;4-(3,4-dichlorophenyl)-7-(7-methyl-[1,2,4] triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;4-(3,4-dichlorophenyl)-7-(8-methyl-[1,2,4] triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;4-(3,4-dichlorophenyl)-7-(2-methyl-[1,2,4] triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2(3H)-one; and an oxide thereof, or a pharmaceuticallyacceptable salt thereof.
 16. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of the compound according to claim
 1. 17. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of the compound according to claim 14.